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Tierärztliche Hochschule Hannover Klinik für Kleintiere
Studies on canine epilepsy: diagnostic workup including advanced imaging techniques and new
treatment modalities
INAUGURAL – DISSERTATION
zur Erlangung des Grades einer Doktorin der Veterinärmedizin
- Doctor medicinae veterinariae -
( Dr. med. vet. )
vorgelegt von
Melanie Jambroszyk
aus Essen
Hannover 2008
II
Wissenschaftliche Betreuung: Univ.-Prof. Dr. med. vet. A. Tipold
Ein Teil des Projektes (Zusatztherapie mit Verapamil) wurde von Frau Univ.-Prof. Dr.
med. vet. H. Potschka, Institut für Pharmakologie, Toxikologie und Pharmazie,
Ludwig-Maximilians-Universität München, mitbetreut.
1. Gutachterin: Univ.-Prof. Dr. med. vet. A. Tipold
2. Gutachter: Univ.-Prof. Dr. med. vet. K. Feige
Tag der mündlichen Prüfung: 22.05.2008
Gefördert durch die Gesellschaft zur Förderung kynologischer Forschung e.V.
III
Meiner Familie gewidmet
„Die Kunst ist, einmal mehr aufzustehen, als man umgeworfen wird.“
Winston Churchill, 1874 – 1965
IV
Teile der hier vorliegenden Arbeit wurden bereits als Kongressbeitrag präsentiert:
ADD ON TREATMENT WITH PHENOBARBITAL AND A P-GLYCOPR OTEIN
INHIBITOR OR LEVETIRACETAM IN DOGS.
M. Jambroszyk1, H. Potschka2, A. Tipold1. 1Department of Small Animal Medicine
and Surgery, University of Veterinary Medicine Hannover, 2Institute of Pharmacology,
Toxicology and Pharmacy, Ludwig Maximilians University, Munich, Germany
In European Society and European College of Veterinary Neurology: Proceedings of
20th Anniversary Symposium “Infectious and Inflammatory Diseases of the Nervous
System in Animals”, Bern 27.-29-September 2007.
Table of content V
Table of content Page
Abbreviations............................................................................................................ VI
1 Introduction..........................................................................................................7
2 Literature review..................................................................................................9
2.1 Idiopathic and symptomatic epilepsy............................................................9
2.2 Pharmacoresistance in epilepsy.................................................................12
3 Material and Methods........................................................................................14
3.1 Evaluation of the distribution and trait of seizures ......................................14
3.1.1 Statistical analysis...............................................................................16
3.2 Treatment Study including treatment with PB and Verapamil- Pre-study ...16
3.3 Treatment Study including treatment with PB and Verapamil- Main-study.18
3.4 Treatment with PB and Levetiracetam .......................................................21
4 Results ..............................................................................................................22
4.1 Actual distribution and classification of seizures ........................................22
4.2 Treatment Study- Outcome of the Pre-Study .............................................30
4.3 Treatment Study- Outcome of the Main Study ...........................................31
4.3.1 Blood evaluation and side effects........................................................33
4.4 Add-on treatment with Levetiracetam.........................................................34
5 Discussion .........................................................................................................35
5.1 First part of the study..................................................................................35
5.2 Second part of the study (Treatment study) ...............................................38
6 Conclusion.........................................................................................................41
7 Summary ...........................................................................................................42
8 Zusammenfassung............................................................................................44
9 References ........................................................................................................47
10 Appendix ...........................................................................................................58
11 Acknowledgements ...........................................................................................76
VI Abbreviations
Abbreviations
AED Antiepileptic Drug
BBB blood brain barrier
CSF cerebrospinal fluid
ECG electrocardiogram
GABA gamma amino butyric acid
ILAE International League Against Epilepsy
KBr potassium bromide
MRI magnetic resonance imaging
MRT Magnetresonanztomographie
PB Phenobarbital
PGP P-glycoprotein
VER Verapamil
Introduction 7
1 Introduction
Epilepsy is one of the most common neurological diseases in dogs (SCHWARTZ-
PORSCHE et al. 1985, JAGGY and BERNARDINI 1998, CHANDLER 2006). It is
characterized by uncontrollable electric discharges of the neurons in the brain
(JAGGY and HEYNOLD 1996) and is defined as a condition of recurrent focal,
complex focal or generalized seizures (LECOUTEUR and CHILD 1989, PODELL et
al. 1996, HEYNOLD et al. 1997). Up to 10% of the dog population with neurological
disorders suffer from seizures of different causes (JAGGY and BERNARDINI 1998).
In veterinary medicine seizures can be categorized due to the etiologic background.
Epilepsy could be divided into three general categories according to the “Commission
on Classification and Terminology of the International League Against Epilepsy”
(ILAE) (ILAE 1989, ENGEL 2006). Concerning idiopathic epilepsy no underlying
causes are detectable during diagnostic work-up (SCHWARTZ-PORSCHE 1984,
JAGGY and BERNARDINI 1998, KNOWLES 1998, LICHT et al. 2002). Symptomatic
epilepsy is induced by an intracranial (secondary intracerebral) or a general
metabolic disease (secondary extracerebral) (JAGGY and HEYNOLD 1996). In
addition, patients, who most likely suffer from symptomatic seizures although no
abnormality could be found after a complete diagnostic work-up, are categorized to
the group of cryptogenic epilepsy (PODELL 1999). Last year at the ACVIM Meeting
in Seattle (25th ACVIM Forum, 2007, Seattle) a consensus statement was presented.
According to this statement the diagnosis of idiopathic epilepsy is confirmed, when
neurological and laboratory examinations are normal.
In the last years several studies have shown that magnetic resonance imaging (MRI)
has the capability to detect abnormalities in the brain more sensitively than computed
tomography (CT) (BRANT-ZAWADZKI et al. 1984, MATHEWS et al. 1989, MODIC
1991, KORTZ 1998, SNYDER et al. 2006). Therefore in human medicine the ILAE
recommends a high quality MRI in every epileptic patient to rule out any secondary
cause for seizure development (KUZNIECKY et al. 2002). In the current study we
evaluated, if MRI examinations are also recommended for every canine patient with
seizures.
8 Introduction
Diagnostic work-up and exclusion of extraneural metabolic diseases is followed by
treatment with antiepileptic drugs. Standard antiepileptic drugs (AED) are
Phenobarbital (PB) and potassium bromide (KBr) (FREY and LÖSCHER 1985,
PEARCE 1990, PODELL 1996, LÖSCHER 2003, GOVENDIR et al. 2005).
Nevertheless, about 30% of dogs with epilepsy are refractory to this
pharmacotherapy (SCHWARTZ-PORSCHE et al. 1985, PODELL and FENNER
1993, TREPANIER et al. 1998, RIECK et al. 2002, MUNANA 2004).
Pharmacoresistance to PB and/or KBr can be defined if no reduction in seizure
frequency of at least 50% is achieved despite adequate serum concentrations of the
AED (TREPANIER et al. 1998, REGESTA and TANGANELLI 1999). Despite the
introduction of several new antiepilepileptic drugs during the last two decades the
incidence of pharmacoresistance remains at a comparable level (REGESTA and
TANGANELLI 1999, BEGHI 2004, ROGAWSKI and LÖSCHER 2004). In veterinary
medicine the use of these new AEDs is limited due to very short half-lives or adverse
side effects (LÖSCHER 2003, GOVENDIR 2005). Furthermore, the costs for some of
these drugs are very high, thus limiting the use of this medication.
In the current study two approaches were pursued: Firstly, the diagnostic workup
including MRI studies in dogs with seizures was evaluated to give a recommendation
for private practice. Therefore, in retrospective part of the study the purpose was to
evaluate the actual distribution of idiopathic and symptomatic epilepsy in 343 patients
with seizures presented at the Department of Small Animal Medicine and Surgery,
University of Veterinary Medicine Hannover, after the introduction of MRI and to
evaluate the use of MRI studies in every patient with seizures.
In a second step a new therapeutic concept in pharmacoresistant dogs with epilepsy
was tested.
Literature review 9
2 Literature review
2.1 Idiopathic and symptomatic epilepsy
Up to 10 % of patients with neurological deficits suffer from seizures of different
causes (SCHWARTZ-PORSCHE et al. 1985, JAGGY and BERNARDINI 1998,
CHANDLER 2006). Diagnosing idiopathic epilepsy is still a demanding challenge,
because all other possible seizure-inducing diseases have to be excluded by the use
of different available diagnostic tools. Dysfunctions like vascular (e.g. stroke) and
inflammatory diseases (e.g. canine distemper encephalitis), trauma, anomaly
(primary hydrocephalus), neoplastic disorders (e.g. brain tumor) or degenerative
diseases (e.g. storage diseases) belong to the group of “secondary intracerebral”
disorders, whereas dysfunctions like hyperglycaemia (e.g. diabetes mellitus),
hypoglycaemia (e.g. insulinoma), hyperammoniaemia (e.g. liver shunt) or
hypothyroidism belong to the “secondary extracerebral” disorders (TIPOLD 1995,
THOMAS 1998, BAGLEY et al. 1999, SNYDER et al. 2006). Precise diagnostic work-
up is necessary to rule out secondary intra- and extracerebral disorders. The
common scheme of complete diagnostic workup in canine epilepsy is shown in
Figure 1. In veterinary medicine the incidence of brain tumors, inflammatory brain
diseases or anomalies is as high as in human medicine (MOORE et al. 1996,
SNYDER et al. 2006). Therefore the MRI should be used as a routine diagnostic tool
in diagnosing idiopathic epilepsy in veterinary medicine as well. This often fails
because of high costs, which result from the required general anaesthesia and
maintenance costs of the MRI (JAGGY and BERNARDINI 1998, BERENDT et al.
1999), but is especially recommended in older individuals (SMITH et al. 2007).
10 Literature review
Figure 1: Scheme of complete diagnostic workup in c anine epilepsy (Source: CVE 2007; 1 (5):
1-24)
In addition to brain lesions causing seizures, postictal MRI changes are described in
human and veterinary medicine (AYKUT-BINGOL et al. 1997, MELLEMA et al.
1999). Postictal changes are regions with hyperintensity in T2-weighted images with
only marginal mass effect (Figure 2). They occur in patients with generalized
physical and neurological
examination
Specific treatment of
internal diseases
Examination of the brain: EEG,
MRI and CSF
Specific treatment of
intracranial diseases
diagnosis of
IDIOPATHIC EPILEPSY
blood cell count, serum chemistry,
X-ray thorax and abdomen,
ultrasound heart/ abdomen… Diagnosis of internal diseases
Exclusion of internal diseases
Diagnosis of intracranial diseases
Exclusion of intracranial diseases
Diagnosis of idiopathic epilepsy
Literature review 11
seizures and cannot be detected in MRI control examinations. These reversible
changes are thought to be caused by a disturbance in the blood-brain-barrier, a local
cytotoxic/vasogenic brain edema or a cerebral dysregulation during seizure activity
(MONTE SECADES et al. 1994, AYKUT-BINGOL et al. 1997, SILVERSTEIN and
ALEXANDER 1998, MELLEMA et al. 1999).
Figure 2: Postictal changes- MRI study of a dog- tr ansversal plane, T2-weighted image,
arrowhead: symmetric hyperintense lesions in the ar ea of hippocampus (Source: Vet Radiol
Ultrasound 1999; 40 (6): 588-595)
12 Literature review
2.2 Pharmacoresistance in epilepsy
One hypothesis for the described pharmacoresistance in patients suffering from
refractory epilepsy is the overexpression of multidrug transporters in the blood brain
barrier (BBB) and in epileptic brain tissue (TISHLER et al. 1995, DOMBROWSKI et
al. 2001, SISODIYA et al. 2002). Recently, we got first evidence that an
overexpression of the multidrug transporter P-glycoprotein (PGP) is also present in
the canine epileptic brain (POTSCHKA, unpublished data).
The physiological function of multidrug transporters is to support the defence
mechanisms of the brain by limiting the influx of a broad spectrum of xenobiotics as
you can see in Figure 3 (FROMM 2000, LEE et al. 2001). P-glycoprotein for example
is normally found in the vicinity of blood vessels, especially on endothelial cell
membranes (RAO et al. 1999) and mainly transports planar, lipophilic, molecular
structures. As the vast majority of the current AEDs have planar and lipophilic
qualities (LEVY et al. 1995) many AEDs are likely to be PGP substrates.
Figure 3: The function of multidrug-transporters li ke P-glycoprotein and their inhibitors for
example Verapamil (Source: The Association of the B ritish Pharmaceutical Industry- ABPI)
Literature review 13
Therefore, overexpression of PGP can explain pharmacoresistance to a broad
spectrum of different AEDs with different mechanisms of action. The overexpression
of P-glycoprotein seems to prevent a sufficient brain penetration of the AEDs and
thus, is hypothesised to limit the AED concentrations reached at the target sites on
epileptic neurons (POTSCHKA et al. 2001, POTSCHKA and LÖSCHER 2001,
LÖSCHER and POTSCHKA 2002).
Experimental data indicate that seizure activity is the major factor inducing a transient
overexpression in the epileptic tissue (ZHANG 1999, SEEGERS et al. 2002).
Another hypothesis of pharmacoresistance in epilepsy is the possibility that GABA-
receptors lose their inhibitory function. In veterinary medicine most of the AEDs act
as a stimulant to the GABA-receptors. Therefore, the administration of AEDs with
completely different mechanisms, such as Levetiracetam (Figure 4), which is binding
at the synaptic vesicle protein (SV2A) instead of GABA-receptors (LYNCH et al.
2004, GILLARD et al. 2006) and which do not act as P-glycoprotein-substrate in
addition, could be recommended.
Figure 4: Chemical structure of Levetiracetam
So far it is not clear, whether a modulation of PGP function can be achieved by co-
administration of Verapamil in order to enhance brain penetration of PB and to
improve the clinical response to PB. The P-glycoprotein modulator inhibitor
Verapamil in combination with PB in patients with refractory epilepsy was expected to
reduce the pathological transporter efflux (POTSCHKA et al. 2002).
14 Material and Methods
3 MATERIAL AND METHODS
3.1 Evaluation of the distribution and trait of seizures
The records of 343 dogs were evaluated. These patients were presented at the
Department of Small Animal Medicine and Surgery, University of Veterinary Medicine
Hannover after introduction of magnetic resonance tomography (MRI) between
01/2004 and 09/2006 by reason of having seizures. The criteria for including patients
in the data collection were the occurrence of focal, complex focal or generalized
seizures and the existence of a physical examination, blood cell count and serum
chemistry. Detailed information about breed, gender, age of presentation, nature of
seizures (focal, complex-focal or generalized seizures, occurrence of clusters/status
epilepticus), age of seizures occurrence for the first time, seizure frequency and
results of physical, neurological and blood examination were recorded. In cases
where additionally ultrasound, MRI and/or an examination of the cerebrospinal fluid
(CSF) were performed, these results were included as well (Table 1).
Table 1: Performed examinations in 343 dogs with se izure activity
Examination number of dogs
physical examination 343
neurological examination 310
blood cell count/serum chemistry 343
thyroid hormone 211
ultrasound abdomen 155
ultrasound heart 112
CSF examination 140
MRI 145
Furthermore the final clinical diagnoses were listed and it was noted if dogs passed
away or had to be euthanized.
Material and Methods 15
After the collection of all data, the patients were divided into two groups to evaluate
the significance of MRI and other further examinations. The cases with a confirmed
diagnosis of idiopathic or symptomatic epilepsy were summarized in Group 1. The
following criteria were used to confirm the different diagnoses. In the case of
idiopathic epilepsy no interictal changes during physical and neurological
examination were found. Blood work, MRI and CSF examination were normal.
Metabolic or toxic disorders were verified by abnormal blood examination and/or
positive metabolic or toxicologic test results. Neoplastic, inflammatory, vascular
disorders and anomalies were diagnosed using MRI in combination with CSF
examination. Histopathological findings contributed to the diagnosis if available to
distinguish inflammatory and neoplastic lesions. Degenerative diseases were
confirmed by histopathological examination.
Group 2 contained all patients with a highly suspicious clinical diagnosis, which could
not be confirmed by further extensive testing. Reasons for incomplete diagnostic
investigation were reluctance of the owner or the dogs died respectively were
euthanized due to bad general condition before finishing diagnostic work-up. In this
group at least a clinical and neurological examination and laboratory testing was
performed as suggested by the consensus statement (25th Annual ACVIM Forum,
2007, Seattle).
Data of group 1 were compared to those of group 2 to evaluate the different
distribution of clinical diagnosis. A correlation between the results of neurological
examination (normal/ abnormal) and MRI findings (normal/ abnormal) was
additionally calculated.
MRI (1 Tesla, Magnetom, Siemens, Siemens AG, Erlangen, Germany) was
performed in 145 patients to exclude symptomatic epilepsy. These image sequences
were re-evaluated by a Diplomat, a Resident of the European College of Veterinary
Neurology and the author. In every case T1-weighted images with and without
contrast medium (Gadolinium) (Magnevist, Schering, Deutschland GmbH, Berlin,
Germany) and T2-weighted images were performed in sagittal, transversal and
dorsal planes. In the cases where FLAIR- and STIR-sequences were available, they
were included into the evaluation. Focus of the re-evaluation of the MRI-images was
16 Material and Methods
to discover and compare the different MRI results as well as to detect possible
postictal changes which arise as hyperintens regions in T2-weighted images and
which are not typical for other brain diseases (MELLEMA 1999). To evaluate, if
postictal changes occur only shortly after seizure events, the time period between
last seizure event and MRI was noted. Control MRIs could not be done in the current
study because of reluctance of the owners to perform two long anaesthesias in dogs
with seizures. Postictal changes were defined as typical diffuse T2 hyperintense
region in the temporal lobes as described by MELLEMA et al. 1999.
3.1.1 Statistical analysis
The comparison of distribution of the clinical diagnoses in group 1 and 2 (confirmed
versus presumptive diagnosis) was made using the two-sided Chi-squared-test. To
prove a feasible correlation between MRI findings and the result of the neurological
examination and the occurrence of postictal changes in MRI, the kappa-index was
calculated. Linear regression gave information about a possible correlation between
the occurrence of postictal changes and the time period between the last seizure
event and performance of MRI. The statistical analysis was performed at the Institute
for Biometry, Epidemiology and Information Processing of the University of
Veterinary Medicine Hannover.
3.2 Treatment Study including treatment with PB and Verapamil- Pre-study
A permit was granted for both parts of the study under animal experiment number
33.42502/05-12.05 on 19 December 2005.
The pre-study was designed to investigate tolerability of a combined treatment with
PB and Verapamil. The combination was tested on 6 beagle dogs two years of age, 3
Material and Methods 17
females and 3 males, with a bodyweight of 11-13 kg.
PB (Luminal/Luminaletten, Desitin, Germany) was applied by oral administration
once daily at a dosage of 4 mg/kg bodyweight. This resulted in a complete dosage of
45-50 mg PB per dog and day in the first part of the study. On day 30 of PB
administration the following initial examinations were performed: clinical and
neurological examination, blood cell count and blood chemistry (Laboratory
Department of Small Animal Medicine and Surgery, University of Veterinary Medicine
Hannover), measurement of blood pressure (NAIS Memoprint, Matsushita Electric
Works), electrocardiogram (ECG) (MAC 5000 marquette and MAC 1200 ST, GE
Medical Systems) and the examination of cerebrospinal fluid (CSF), which included a
cell count, the measurement of glucose concentration, total protein and PB
concentration in the CSF (Laboratory Department of Pharmacology and Toxicology,
University of Veterinary Medicine Hannover). CSF samples were taken under general
anaesthesia in lateral recumbency by puncture of the Cysterna magna.
All six dogs additionally received Verapamil twice daily (Verapamil-ratiopharm N 80,
Ratiopharm, Germany) at a dosage of 6.2–7.3 mg/kg bodyweight starting on day 32
after the beginning of the administration with PB. The Verapamil administration
resulted in a complete dosage of 160 mg per dog and day. On day 13 of this
combined application all above mentioned examinations and the measurement of PB
concentration in the CSF were repeated. After that the Verapamil administration was
stopped and PB administration was increased to 10 mg/kg bodyweight once a day to
determine whether adverse effects in patients treated with a high PB dosage might
occur. This resulted in a dosage of 115–130 mg PB per dog and day. Thirty days
after increasing the PB administration the dogs received again an add-on treatment
with Verapamil (6.6-7.3 mg/kg twice daily, 160 mg per dog and day). Forty-three days
following the increase in the PB dosage all examinations were repeated except for
the sampling and analysis of CSF as shown in Figure 5.
18 Material and Methods
Figure 5: Study design pre-study
legend: PB= Phenobarbital, VER= Verapamil, bw= body weight
3.3 Treatment Study including treatment with PB and Verapamil- Main-study
The main study included 11 dogs from different breeds, which were considered to be
non-responders to PB treatment (Table 2). For inclusion in the study the dogs had to
fulfill the following criteria: generalised seizures (single generalised seizures,
clusters, status epilepticus), no benefit or poor seizure control despite a high serum
level of PB. The dogs had to display a seizure frequency of at least one seizure/
month and had to be treated only with PB, resulting in an adequate serum level
within the therapeutical range (65-130 µmol/l). Data concerning seizure frequency of
the previous 4 months were available and physical and neurological examinations
had to be without distinctive features. Dogs were examined according to the study
design shown in Figure 6.
0 days 30 32
first
examination
45
second
examination
75 88
third
examination
VER add-on
treatment
PB treatment
4mg/kg bw
PB treatment alone
10 mg/kg bw
VER add-on
treatment
Material and Methods 19
Figure 6: Study design main-study, legend: PB= unde r Phenobarbital treatment alone
The initial examination included the same tests as in the pre-study: physical and
neurological examination, blood cell count and serum chemistry, measurement of
blood pressure and ECG. In cases with bradycardia, cardiac murmur or an irregular
heartbeat, blood pressure under reference range and/or an abnormal ECG, patients
were not allowed to participate in the study because of a potential for increased side
effects of Verapamil.
After giving the owners general instructions and having them sign a contract the
Verapamil administration started at a dosage of about 1 mg/kg twice daily additionally
- 4 - 3 - 2 - 1 1 2 3 4
control examinations
1 2 3 4
Levetiracetam add - on treatment
months
months
PB treatment Verapamil add- on treatment
initial examination
20 Material and Methods
to the PB treatment. The Verapamil dosage was reduced in comparison to the pre-
study since the first study participant developed severe bradycardia as an adverse
side effect. Every four weeks after the first Verapamil administration controls were
performed and the initial examinations were repeated four times. Before beginning
with the co-administration of PB and Verapamil and at the last control examination
the PB serum level was measured (Alomed, Radolfzell-Böhringen). Following the
fourth examination participation in a long-term study was optional for the owners, if
the dog responded well to the combined treatment and no side effects occurred.
Dogs with a reduction in seizure frequency of at least 50 % during the period of
combined treatment with PB and Verapamil compared to the 4-month period without
Verapamil were classified as Verapamil-responders. The following data were
evaluated: number of Verapamil-responders, development of seizure severity,
seizure duration and possible side effects.
Material and Methods 21
3.4 Treatment with PB and Levetiracetam
In Verapamil-non-responders an add-on treatment with Levetiracetam (10-15 mg/kg
three times daily) was tested following discontinuation of Verapamil. If no seizure
reduction was observed in response to this initial dosage the Levetiracetam dosage
was increased to 20 mg/kg bodyweight three times daily. Additional diagnostic work-
up such as computed tomography (CT), magnetic resonance imaging (MRI) and CSF
analysis was performed in half of the cases to rule out symptomatic epilepsy. In the
other dogs further examinations could not be performed because of reluctance of the
owners.
Table 2: Patient information and Phenobarbital plas ma level before and after combined
treatment with Verapamil
Case Breed Gender
Weight
(kg)
Age of
1st
seizure
(yr)
Age at
study entry
(yr)
seizure
type
length of PB
medication before
study entry
PB plasma
pre VER add-
on
PB plasma
after the
study
Additional
diagnostic
workup
1 GS m 30,5 1,75 3,5 tc 20 90.1 µmol/l
2 H f 37,5 3,1 4,5 tc, foc 11 109.2 µmol/l CT, CSF
3 AT m 9,3 1,75 2,25 tc 5 135 µmol/l
4 CB f 16 2,75 3,75 tc 8 135.9 µmol/l CT, CSF
5 BP f 13,3 4,5 7,5 tc 34 158.2 µmol/l MRI, CSF
6 S f 40 1,8 3,5 tc, foc 20 147.5 µmol/l 160 µmol/l
7 CB m 42 4,2 7,1 tc 36 95 µmol/l 110 µmol/l
8 CB m 41 1 5 tc 42 65 µmol/l 124 µmol/l
9 BP m 14 3,25 7,25 tc 45 174 µmol/l 164 µmol/l
10 FB f 14 0,9 1,2 tc 4 89 µmol/l 87 µmol/l MRI, CSF
11 CB f 15,5 1,5 3,2 tc 21 180 µmol/l 134 µmol/l MRI, CSF
legend: GS= Gordon Setter, H= Hovawart, AT= Austral ian Terrier, CB= Crossbreed, BP= Bergé
de Pyrenée, S= Giant Schnauzer, FB= French Bulldog, m= male, f= female, yr= years, tc=
generalised tonic-clonic seizures, foc= focal seizu res, PB= Phenobarbital, VER= Verapamil,
MRI= magnetic resonance imaging, CT= computed tomog raphy, CSF= cerebrospinal fluid
analysis, = drop out
22 Results
4 RESULTS
4.1 Actual distribution and classification of seizures
A total of 343 dogs suffering from generalized, focal or complex focal seizures met
the criteria for inclusion in the study. Of these 343 dogs, 150 dogs (43.7%) were
female and 103 dogs (56.3%) as shown in the figure 7.
Figure 7: Distribution of gender
legend: f= intact female, fn= neutered female, m= i ntact male, mn= neutered male
Over eighteen breeds were represented in addition to 77/343 crossbred dogs
(22.5%). The distribution of frequently occurring breeds is shown in figure 8; large
breed dogs were seen more frequently than small breed dogs. Information about the
age when the first seizure appeared in the dogs could be gathered in 337 cases.
Fourty three dogs (12.8%) were younger than one year, 91 dogs (27%) were older
than six years and the main part of 203 dogs (60.2%) were between one and six
years old.
distribution of gender
f
fn
m
mn
Results 23
5.2%
22.5%
48.3%4.7%
4.7%
4.1%
4.1%
3.2%
3.2%
miscellaneous breeds
Crossbreed
Golden Retriever
Dachshund
Jack Russel Terrier
Labrador Retriever
German Shepherd
Schnauzer
Beagle
Figure 8: Distribution of different breeds sufferin g from seizure activity.
The character of the seizures was evaluated in all cases. The main part (304 dogs;
88.6%) suffered from generalized seizures (tonic-clonic, tonic, clonic) whereas a
differentiation between primary and secondary generalized seizures could not made
retrospectively. Fourteen dogs (4.1%) suffered from focal and 8 (2.3%) dogs suffered
from complex-focal seizures exclusively. Ten dogs (2.9%) were afflicted with the
combination of generalized and focal seizures, whereas 2 dogs (0.6%) suffered from
the combination of focal and complex-focal seizures. Only in 1 dog (0.3%) all three
forms of seizuring (generalized, focal and complex-focal) occurred. Seizure
frequency could be evaluated in 328 dogs. The other dogs were admitted because of
sudden onset of clusters or status epilepticus. Most of the dogs (124/328; 37.9%)
had only 2-3 seizures at the time of the neurological consultation and the exact
frequency could not be determined. The seizure frequency of the other 204 dogs is
described in Figure 9.
Furthermore, 49.9% (171/343) of the whole study population suffered from cluster
runs whereas 12.5% (43/343) experienced a status epilepticus in life before. Of the
whole patient population 34 dogs (9.9%) had to be euthanized because of the
24 Results
severity of their seizures and the seizure frequency, and 4 patients (1.2%) died due
to bad general condition.
Figure 9: Seizure frequency of 204 dogs
In every patient blood cell count and serum chemistry was performed. In 63.3% of
the population (217/343) both examinations were unremarkable whereas in 36.7%
(126/343) different abnormalities could be found. The diagnoses of dogs with
metabolic-toxic diseases and seizure activity are summarized in table 3.
0
10
20
30
40
50
60
70
dogs
monthly weekly every second week 1-2/ year <1/ year daily
Results 25
Table 3: Dogs with metabolic-toxic diseases and sei zure activity (confirmed diagnoses)
diagnosis number of dogs
intoxication 16
hypothyreosis 10
insulinoma 6
Cushing’s disease 4
diabetes mellitus 4
liver shunt 3
sick sinus syndrom 2
hypoparathyoidism 2
Addison’s disease 1
hypoxy 1
hyocalemia after birth 1
others 1
total 50
In general the whole population could be divided into two groups. 212 patients were
summarized in group 1 (61.8%) and the clinical diagnosis was considered to be
confirmed according to the described criteria. In group 2 (131 dogs) diagnoses were
only presumed because of incomplete diagnostic work-up. Two-sided Chi-squared-
test could show a significant different distribution of etiological background
(p=0.0005). In group 2 a suspicion of idiopathic epilepsy was more frequently
diagnosed, than in cases with complete diagnostic work-up of group 1. Furthermore,
diseases like anomalies, vascular and degenerative diseases were not diagnosed in
group 2. In figure 10 the distribution of different disease categories causing seizures
is shown in a comparative way for group 1 and 2.
26 Results
A: group 1
different disease categories- confirmed diagnoses
idiopathic
vascular
inflammatory
trauma
anomaly
metabolic-toxic
neoplastic
degenerative
B: group 2
different disease categories- presumed diagnoses
idiopathic
vascular
inflammatory
trauma
anomaly
metabolic-toxic
neoplastic
degenerative
Figure 10 A+B: Different disease categories of grou p 1- confirmed and group 2- presumed
diagnoses
Neurological examination was performed in 310 dogs. The other cases had to be
sedated because of severe seizure activity. In 214 of the 310 dogs, the neurological
examination was unremarkable whereas in 96 dogs neurological deficits occurred
such as ataxia, proprioceptive deficits, absent menace response, vestibular signs,
strabismus/nystagmus, anisocoria, hypermetria, circling, opisthotonus, and/or
paraparesis/ tetraparesis. In 145 dogs a neurological examination as well as a MRI
examination was performed. In these cases the result of the neurological
Results 27
examination (normal/ abnormal) was compared with the results of MRI (normal/
abnormal). Kappa-index was calculated and a slight correlation existed (kappa-index
0.1358). Ninety three of the 145 dogs did not show neurological deficits and 76 of
them had a normal MRI additionally. Nevertheless, in 17 dogs MRI abnormalities
could be found despite a normal neurological examination. In these 17 cases either
an intracerebral neoplasia or an inflammatory disease was detected. In contrast,
neurological deficits could be shown in 52 of the 145 dogs. Sixteen of them had
abnormal findings in MRI whereas 36 dogs had a normal MRI. These results are
illustrated in Table 4.
Table 4: Correlation between the results of neurolo gical examination and MRI
neurological examination unremarkable neurological examination abnormal number of dogs: 93 number of dogs: 52
normal MRI results
abnormal MRI results
normal MRI results
abnormal MRI results
76 17 36 16
Neurological deficits were found in 36 cases with normal further examinations. In
these cases these signs did not resolve in all cases until 1 to 5 days. Therefore they
were not considered as postictal findings in all of these cases.
In addition to the evaluation of the diagnoses of these 145 MRI-series, attention was
turned to the existence of postictal changes in MRI-sequences. Presumed postictal
changes occurred in 10/145 cases (Figure 11). There was no correlation between
postictal changes and normal or abnormal MRI (neoplasia, inflammatory lesion,
anomaly) (kappa-index -0.0640).
28 Results
Figure 11: Presumed postictal changes: MRI of a dog - transversal plane, T2-weighted image
Albeit a certain tendency could be seen, a correlation between the occurrence of
postictal changes and the period between the last seizure event and performance of
the MRI (p=0.1911) could not be proven. In table 5 the time period between the last
seizure event and the MRI performed in cases with postictal changes is listed.
Table 5: patients with postictal changes in MRI- da ys between last seizure event and performed
MRI
Patient days between seizure event and MRI
1 4
2 4
3 1
4 1
5 16
6 2
7 2
8 8
9 1
10 1
Results 29
Examination of cerebrospinal fluid (CSF) was performed in 140 dogs. 90% of the
dogs (126/140) had a normal CSF without an elevated number of cells (0-2 cells/µl).
Six dogs (4.3%) had a slightly increased (3-10 cells/µl) and 8 dogs (5.7%) had a
moderate to severe increased number of cells in CSF.
An overview about the context between the age at onset of seizures and the results
of the neurological examination, the CSF analysis and the performed MRI in 135
dogs is shown in Table 6.
The probability is higher in dogs older than 6 years of age that a normal neurological
examination is accompanied by abnormal MRI results.
Table 6: results of neurological examination, exami nation of the CSF and the existence of
abnormal MRI findings in 135 patients
number of dogs age at onset of
seizures
results neuro
examination result CSF analysis normal MRI
results abnormal MRI
results
< 1y abnormal abnormal 1 1
abnormal normal 2 1
normal abnormal 0 0 normal normal 6 1
1y > 6y abnormal abnormal 2 2 abnormal normal 17 4
normal abnormal 0 1
normal normal 40 5
> 6y abnormal abnormal 1 0
abnormal normal 8 5
normal abnormal 3 1
normal normal 25 9
30 Results
4.2 Treatment Study- Outcome of the Pre-Study
All beagle dogs were in good constitution and alert during the whole study period.
Between days 32 to 40 the dogs developed slight diarrhoea. Initial and control
examinations were altogether unremarkable. Bradycardia (64 heartbeats per minute)
was observed during the third control examination in dog 1. Furthermore, a decrease
in blood pressure was found in three of the dogs during the course of the study. In
ECGs no abnormal findings could be observed (Table 7).
Table 7: Count of heart rate and results of blood p ressure measurement in six healthy beagle
dogs
Dog Gender Heart rate blood pressure
1st
examination
2nd
examination
3rd
examination
1st
examination
2nd
examination
3rd
examination
1 m 112 100 64 174/129 131/75 112/80
2 f 132 140 120 160/124 131/105 138/109
3 m 100 140 116 170/133 167/107 157/85
4 m 100 84 88 144/99 133/89 135/81
5 f 120 120 106 175/107 168/112 197/135
6 f 100 132 100 192/111 133/90 120/97
legend: m= male, f= female, heart rate= heartbeats per minute, blood pressure= systolic arterial
blood pressure/ diastolic arterial blood pressure i n mm/Hg
The CSF examinations were unremarkable. Cell count, glucose concentration and
total protein were all within the reference ranges in both CSF samples of each dog.
The measurement of PB concentration in serum and CSF did not result in any
elevation of PB concentration in CSF after the combined treatment with PB and
Verapamil over 14 days (Table 8).
Results 31
Table 8: Phenobarbital level in serum and cerebrosp inal fluid before (1 st examination) and 13
days after combined treatment of Phenobarbital and Verapamil (2 nd examination) in six healthy
beagle dogs
dog 1st examination 2nd examination
PB plasma (µg/ml) PB CSF (µg/ml) PB plasma (µg/ml) PB CSF (µg/ml)
1 8,02 5,77 8,65 5,52
2 11,22 5,40 11,63 6,24
3 12,86 8,05 14,41 7,72
4 12,03 8,18 13,00 8,24
5 13,11 7,76 10,75 6,29
6 11,69 6,68 12,94 7,44
legend: PB= Phenobarbital, CSF= cerebrospinal fluid
Blood examinations: three dogs (2, 5 and 6) had slightly elevated leukocytes (13.0-
14.2 103/µl, reference range 6.0-12.0 103/µl) at the last control examination. Two of
these dogs (5, 6) additionally developed decreased haemoglobin concentration under
reference range (14.1 g/dl, 11.9 g/dl, reference range 15.0-19.0 g/dl), which was
combined with a decreased hematocrit of 33 % (reference range 40.0-55.0%) in dog
6. In addition, five of the six dogs showed slightly elevated liver enzymes (ALT 69-
419 U/l, reference range < 50 U/l; GLDH 98,6 U/l, reference range < 6 U/l; ALP 238-
337 U/l, reference range <150 U/l) at the third blood examination. Both previous
blood examinations had revealed that all values had been within the reference range
before.
4.3 Treatment Study- Outcome of the Main Study
Patients’ medium age at the beginning of the first seizures was 2.4+0.8 years.
Medium bodyweight was 24.8+8 kg. All these dogs were considered to be
pharmacoresistant to PB and had at least generalised seizures every four weeks.
32 Results
Further information concerning all patients such as age at first seizure, age at study
entry, seizure type, length of time previously treated with PB, serum concentration at
study entry and after the study period of four months is provided in Table 2.
Six of the eleven patients completed the four-month observation period with
combined treatment with PB and Verapamil. Three dogs discontinued the study
because they developed heavy cluster seizures (Figure 12). In Patient 1 these
clusters started 7 days after beginning with add-on therapy with Verapamil directly.
Clusters had never appeared before in this patient. In Patient 2 cluster seizures had
occurred before the study, but after 6 weeks of combined treatment a run of clusters
of higher severity than before was observed despite seizure frequency having
decreased from 4.5 to 2 seizures/ month. In Patient 3 cluster seizures had been
known as well, but after 8 weeks of combined treatment heavier cluster seizures with
a higher number of generalised seizures/ 24 hours appeared in this patient, too. The
seizure frequency increased from 2 to 2.3 seizures/ month. All three patients had to
receive intravenously barbiturates to stop cluster seizures. Verapamil treatment was
discontinued in these cases and Levetiracetam add-on treatment was recommended.
In addition, two more patients did not complete the study because seizure frequency
did not change satisfactorily. Patient 4 stopped the study after 10 weeks. The seizure
frequency of this patient decreased from 2 to 1.3 seizures/ month. However, the
intensity and duration of the seizures increased. Patient 5 left the study after 9 weeks
because seizure frequency increased from 1.6 to 2.3 seizures/ month. The remaining
six patients completed the arranged observation period. One out of these six dogs
was a responder (Patient 7). The other five dogs were non-responders. The medium
seizure frequency before the beginning of the combined treatment with PB and
Verapamil was 1.4 seizures/ month (range 0.8 to 2.3) which increased to 1.8
seizures/ month (range 1.4 to 2.3). Furthermore, the intensity of the seizures
worsened at the end of the observation period in two of the dogs. In the dogs
suffering from cluster seizures before the study the number of seizures per day could
not be reduced with add-on treatment with Verapamil.
Results 33
Figure 12: Seizure frequency before and during Vera pamil and Levetiracetam add-on treatment
legend: PB= under Phenobarbital treatment alone
4.3.1 Blood evaluation and side effects
The PB serum concentration was evaluated before and after the four-month study
period. PB serum levels were not increased (Table 2). Regarding side effects in the
circulatory system severe bradycardia of 35 heartbeats per minute occurred in
Patient 11 two days after beginning with add-on therapy with Verapamil at a dosage
of 2 mg/kg bodyweight twice daily. The dosage was immediately lowered to 1 mg/kg
bodyweight twice daily. After this reduction the dog was in good constitution and
frame of mind and all circulatory values were in reference ranges during the further
study period. In two more patients a slight decrease in blood pressure could be
observed. However, values were still within the reference range and no clinical signs
occurred. Complete blood cell count and serum chemistry were performed in all
patients at every control examination. With the exception of a slight increase in liver
0
1
2
3
4
5
1 2 3 4 5 6 7 8 9 10 11
patients
seiz
ures
/ mon
th
PB Verapamil add-on Levetiracetam add-on Cluster
34 Results
enzymes in four and an increase of eosinophilic granulocytes in two (1760 – 1900/µl,
reference range < 1500/µl) out of eleven patients no further changes were observed.
One patient developed slight anaemia (haemoglobin 14.1 g/dl, hematocrit 39%,
erythrocytes 5.74 106/µl, reference range 6.0-9.0 106/µl) without clinical signs.
4.4 Add-on treatment with Levetiracetam
The 8 Verapamil non-responders (dogs 2, 3, 4, 5, 6, 9, 10 and 11) were treated with
Levetiracetam additionally to PB after Verapamil had been discontinued. As initial
dosage the dogs received 10-15 mg/kg bodyweight three times daily (VOLK et al.
2007).
If seizure frequency was not reduced for at least 50 % the dosage of Levetiracetam
was increased to 20 mg/kg bodyweight three times daily.
A subpopulation of 3 out of these 8 dogs (dogs 3, 4 and 10) could be classified as
Levetiracetam-responders. In Patient 3 seizure frequency was reduced from 2.1 to
0.5 seizures/ month. However, the number of cluster seizures could not be reduced.
The seizure frequency in Patient 4 decreased from 2 to 1 seizure/ month. In addition,
the severity of the seizures could also be reduced subjectively. The third responder
was Patient 10. After beginning with Levetiracetam add-on therapy no more seizures
for the four-month observation period appeared. However, after seven months cluster
seizures occurred once despite Levetiracetam treatment. The other five dogs had to
be classified as non-responders. The medium seizure frequency before the
beginning of the combined treatment with PB and Levetiracetam had been 2.25
seizures/month (range 1.5 to 3.8) which increased to 2.7 seizures/ month (range 1.8
to 3.9). The subjectively examined severity of the seizures could be reduced in all
cases. In the dogs suffering from cluster seizures the number of seizures per day
could not be reduced by using Levetiracetam as add-on therapy.
Discussion 35
5 Discussion
5.1 First part of the study
Epilepsy is one of the most common neurological diseases in dogs (SCHWARTZ-
PORSCHE et al. 1985, JAGGY and BERNARDINI 1998, CHANDLER 2006). The
etiological background of seizures is categorized into three different classes - the
idiopathic, the symptomatic and the cryptogenic epilepsy. In the idiopathic epilepsy
no detectable causes can be demonstrated after complete diagnostic work-up. The
symptomatic epilepsy is induced by an intracerebral or extracerebral disease and
cryptogenic epilepsy consists of patients in which symptomatic epilepsy is assumed
though no abnormalities are detectable (PODELL et al. 1995).
First goal in the present study was to analyse a large group of patients suffering from
seizures and classify the etiological background of the seizures according to the
Vitamin D-scheme (JAGGY 2005). All the patients were divided into two groups. In
group 1 in 212 patients a confirmed diagnosis could be established. The other 131
patients in group 2 did not undergo complete diagnostic work-up and etiologic causes
could only be presumed.
Regarding our data it can be stated, that 50 % of the patients with confirmed
diagnosis suffered from idiopathic epilepsy. In the other 50 % of the patients seizures
were a symptom of another primary disease. MRI diagnosis, established by the
examination of a large number of cases, did not change the figure, since the number
of patients with idiopathic epilepsy is similar to the number in former studies, which
range from 25 % over 40 % to 53 % of all epileptic dogs (PODELL et al. 1995,
JAGGY and BERNARDINI 1998, BERENDT and GRAM 1999). In our study about 24
% of the patients with symptomatic epilepsy suffered from metabolic-toxic diseases
like liver-shunts, hypothyroidism and other organic disorders, about 10 % had brain
tumors and 8.5 % suffered from inflammatory brain diseases. In our case load more
dogs had brain tumors than it was observed in most of previous studies (MOORE et
al. 1996, SNYDER et al. 2006). The same could be found for metabolic-toxic
36 Discussion
diseases (PODELL et al. 1995). The introduction of MRI seems to enhance the
diagnosis of brain tumors. Most of the brain tumors were observed in German
Shepherds (4/11 dogs) and Boxers (3/5 dogs). This matches with former studies
where Boxers were most affected amongst other breeds (HEIDNER et al. 1991,
BAGLEY et al. 1999). The German Shepherd is one of the most common breeds in
Germany with 16.000 to over 29.000 puppies per year in the last 10 years
(VERBAND FÜR DAS DEUTSCHE HUNDEWESEN, 2007) which could explain the
high number of German Shepherds with brain tumors. Anomalies were found only in
pure bred dogs and never appeared in any crossbred dog. Finally, we could not rule
out cryptogenic epilepsy in patients with an abnormal neurological examination
despite a normal CSF analysis and a normal MRI. This is in agreement with the study
of Berendt and Gram, 1999.
We compared group 2 (with a presumed diagnosis) with group 1 (with a confirmed
one). The results of the two-sided Chi-squared-test show that the distribution of the
differential diagnoses between the two groups is significant different. In group 2, 75%
of the dogs were classified to have idiopathic epilepsy, in only 25% symptomatic
epilepsy was suspected. Therefore most probably neoplastic, inflammatory and
metabolic-toxic diseases were underdiagnosed. Furthermore no anomaly and no
vascular diseases were suspected in group 2. In conclusion we can propose that a
complete diagnostic work-up is highly recommended for an exact diagnosis of the
cause for occurring seizures. Beyond we tested the capability of the neurological
examination to predict abnormalities in MRI or CSF examination respectively to
predict idiopathic epilepsy. Calculated kappa-index shows only a slight correlation.
Nevertheless, we could show that an unremarkable neurological examination is
mostly accompanied by a normal MRI, whereas abnormal MRI findings mainly occur
if the neurological examination is abnormal. This result confirms a former study
where correlation between the age and the results of neurological examination, CSF
analysis and MRI were tested (BUSH et al. 2002). Therefore, it can be proposed that
CSF analysis and MRI is indicated in dogs with seizures particularly if the
neurological examination is abnormal. Only in dogs older than 6 years of age a
tendency could be shown that MRI findings occur despite a normal neurological
Discussion 37
examination. According to the consensus statement, ACVIM, Seattle 2007, idiopathic
epilepsy could be diagnosed already by normal physical and neurological
examination and an unremarkable blood work. We could show in our study that older
dogs more frequently had MRI abnormalities despite a normal neurological
examination. Therefore MRI is recommended especially for dogs with seizures over 6
years of age even if financial aspects have frequently to be considered in private
practice (JAGGY and BERNARDINI 1998).
Concomitant we wanted to discover the occurrence of presumed postictal changes.
Postictal changes are described as hyperintens regions in T2-weighted images
without special mass effect. Their specific feature is their disappearance in control
MRI. It is thought that postictal changes are caused by a disturbance in the blood-
brain-barrier, a local cytotoxic/vasogenic brain edema or a cerebral dysregulation
during seizure activity (MONTE SECADES et al. 1994, AYKUT-BINGOL et al. 1997,
SILVERSTEIN and ALEXANDER 1998, MELLEMA et al. 1999). In our study
presumed postictal changes were found in 10 patients while MRI sequences were re-
evaluated. We had not the possibility to confirm that these changes disappeared in
control MRIs. Due to the fact that no control MRIs had been done, the occurrence of
postictal changes could only be assumed and interpretation of postictal changes can
be subjective. Re-evaluation was performed in a blinded way by a Diplomat and a
Resident of the European College of Veterinary Neurology to minimize the level of
error and evaluate in the most possible objective way. The occurrence of postictal
changes seems to be more probable when MRI is performed directly after the last
seizure event. However, calculating the linear regression in the present study no
significant correlation between the occurrence of postictal changes and the time
period between the last seizure event and performance of MRI could be seen. In our
study presumed postictal changes were found, when MRI studies were performed
contemporary 1 to 4 days after the last seizure event. Altogether postictal changes
seem to be rare findings compared to the total number of performed MRIs in our
study.
38 Discussion
5.2 Second part of the study (Treatment study)
In veterinary medicine about 30 % of the patients who suffer from epilepsy are
refractory to the treatment with common AEDs, such as PB and KBr (SCHWARTZ-
PORSCHE et al. 1985, PODELL and FENNER 1993, TREPANIER et al. 1998,
RIECK et al. 2002, MUNANA 2004).
In former studies an overexpression of multidrug-transporters in the BBB and in brain
tissue was identified both in rats and humans with refractory epilepsy (TISHLER et al.
1995, DOMBROWSKI et al. 2001, SISODIYA et al. 2002, POTSCHKA et al. 2004,
VOLK and LÖSCHER 2005). It is hypothesised that the overexpression of
transporters such as P-glycoprotein can limit brain penetration rates of AEDs
including PB. Refractoriness to AEDs can be the consequence of insufficient
concentrations at the target sites in the epileptic brain. A few experimental studies
with epileptic rats with pharmacoresistant or difficult-to treat epilepsy were performed
in which the efficacy of P-glycoprotein-inhibitors could be shown, which preclude the
pathological transporter efflux of AED (CLINCKERS et al. 2005, BRANDT et al. 2006,
VAN VLIET et al. 2006 ).
To tie in with these former experimental studies in rats it was the aim of our study to
evaluate the efficacy and tolerability of the co-administration of the P-glycoprotein-
inhibitor Verapamil with PB in dogs who suffer from naturally recurrent severe seizure
activity.
To fulfill the inclusion criteria of the study only dogs with refractory epilepsy were
examined. Generalised seizures occurred at least every four weeks, serum levels of
PB had to be within the normal and high range respectively. In a pre-study a good
tolerability of combination using higher dosage of PB and Verapamil than usually
applied, was demonstrated. No severe side effects occurred in the six beagle dogs
except for one of them which developed slight bradycardia. However, PB levels in
CSF did not increase after add-on treatment with Verapamil. It is possible that the
inhibition of the P-glycoprotein only affects PB concentrations in epileptic foci of
affected patients. VAN VLIET et al. (2007) showed in a recent study an increased
Phenytoin level after inhibition of P-glycoprotein with Tariquidar, which is a highly
Discussion 39
selective inhibitor, especially in brain regions with PGP-overexpression. This would
explain why the PB levels in CSF did not increase in the six healthy beagle dogs. On
the other hand, it is also possible that competitive inhibitors of the low affine first
generation, like Verapamil, could not inhibit P-glycoprotein efficiently at dosages
which are tolerable in dogs.
In our main-study population only one responder could be observed out of eleven
patients, whose seizure frequency improved up to 75 % in the designed observation
period and the last five months of the long-term follow-up. Five of the included
patients discontinued the intended observation period due to ineffectiveness of the
treatment. Three out of these five patients developed severe cluster seizures. In the
five remaining patients who completed the four-month observation period a
significant decrease in the seizure frequency did not occur. In general, a worsening
of the seizure severity could be observed subjectively by the owners in most of the
participants. In one patient mutual reaction concerning the circulatory system
occurred in form of severe bradycardia which disappeared after the dosage of
Verapamil was decreased. All the other patients were in good constitution over the
whole study period and no further side effects were seen.
The reason why the seizure frequency could not be reduced by treatment with the P-
glycoprotein inhibitor Verapamil in this study is not known. A possible explanation
would be that the Verapamil dosage in our study was too low to inhibit the
overexpressed multidrug transporters. Although no severe adverse effects occurred
in the beagle group of the pre-study, which were treated with a higher dosage of
Verapamil, we could not increase the Verapamil dosage in the epileptic patients due
to life-threatening side effects concerning the circulatory system as was the case in
Patient 11. The low dosage might have prevented the PB level reaching the effective
levels in the affected brain tissue to advance the accumulation of the AED in epileptic
foci. Noncompetitive inhibitors of the third generation such as Tariquidar (BRANDT et
al. 2006, VAN VLIET et al. 2007) might be more effective. This has also been
indicated by studies with P-glycoprotein-inhibitors in human cancer patients.
It is not clear, if either the medication failed or multidrug transporter overexpression
did not contribute to refractoriness in most of the dogs included in the study.
Another presumptive hypothesis in refractoriness is that the GABA-receptors lose
40 Discussion
their inhibitory function in general (DEISZ 2002, BECK 2007). The GABA-receptor is
the most important inhibitory receptor in the central nervous system. The
neurotransmitter gamma-aminobutyric acid (GABA) ligates on GABA-receptors which
induces an opening of the potassium channels causing a hyperpolarisation of the cell
membrane. Furthermore, calcium channels are blocked so that no more excitatory
transmitters can be discharged. Therefore, an achieved adequate PB level due to an
inhibition of the multidrug transporters could not have a positive effect concerning the
seizure frequency if the GABA-receptors lose their inhibitory function. Therefore,
eight Verapamil non-responders were treated with Levetiracetam as the add-on
therapy after Verapamil had been discontinued. Levetiracetam is an AED which has
recently been developed in human medicine. It is binding at the synaptic vesicle
protein (SV2A) instead of at GABA-receptors (LYNCH et al. 2004, GILLARD et al.
2006). Therefore, Levetiracetam is the only AED whose mechanism of action is
completely different to that of the common AEDs. Furthermore there is evidence from
rat studies that Levetiracetam is not a substrate of P-glycoprotein (POTSCHKA et al.
2004).Three out of eight dogs could be classified as Levetiracetam-responders in PB
pharmacoresistant dogs. In two dogs a reduction in seizure frequency of 50 % and
75 %, respectively could be achieved. One of these patients was even seizure-free
over a seven-month period before cluster seizures occurred. Thus, in accordance
with the study from VOLK et al. (2007) Levetiracetam proved to be a useful add-on
medication only in a subpopulation of PB non-responders. However, VOLK et al.
showed that the development of tolerance is a problem not only in treatment with
Zonisamid (VON KLOPMANN et al. 2005, VON KLOPMANN et al. 2007), but also in
treatment with Levetiracetam.
When interpreting the data of the present study the applied inclusion criteria (normal
physical and neurological examination and normal blood work) were used according
to the consensus statement, ACVIM, Seattle, 2007. In five patients, additional tests
such as MRI, CT and CSF analysis were performed to rule out intracranial diseases
as other causes than idiopathic epilepsy responsible for the severe
pharmacoresistance. In the remaining cases intracranial diseases could not be
dismissed completely as a reason for pharmacoresistance.
Conclusion 41
6 Conclusion
In summary, the performance of imaging techniques such as CT and MRI seems to
enhance the diagnosis of symptomatic epilepsy and is recommended in patients
suffering from seizures. The age and the results of neurological examination could be
used to predict if MRI is recommended and could be abnormal. Postictal changes are
a rare finding and occur mostly when the time spare between MRI performance and
last seizure event is under 4 days.
The current study indicates also that the P-glycoprotein-inhibitor Verapamil is not
appropriate for preventing pathological efflux of PB in most dogs at the dosage used.
Since at a higher dosage severe cardiac side effects were seen, this add-on
medication cannot be recommended in dogs. It is not clear, if either the medication
failed or multidrug transporter overexpression did not contribute to refractoriness in
the dogs included in this study with the exception of one case. In general,
pharmacoresistance is regarded as a multifactorial phenomenon in an entire patient
population. Subpopulations, as found in this small study, may exist. Therefore, single
cases might respond to P-glycoprotein-inhibitors or to medications not acting on the
GABA-receptor. Levetiracetam seems to be a valuable add-on medication in a
subpopulation of canine non-responders to phenobarbital.
42 Summary
7 Summary
Jambroszyk, Melanie:
Studies on canine epilepsy: diagnostic workup including advanced imaging
techniques and new treatment modalities
Up to 10% of the dog population with neurological disorders suffer from seizures of
different causes. Because further studies showed that the incidence of symptomatic
epilepsy caused by brain tumors, inflammatory brain diseases or anomalies is as
high as in human medicine, MRI is recommended as a routine diagnostic tool in
diagnosing idiopathic epilepsy in veterinary medicine.
The purpose of this retrospective part of the study was to evaluate the actual
distribution of idiopathic and symptomatic epilepsy in 343 patients with seizures
presented at the Department of Small Animal Medicine and Surgery, University of
Veterinary Medicine Hannover, after the introduction of MRI.
Two-sided Chi-squared-test could show a significant different distribution of
etiological background (p=0.0005). In presumed cases a suspicion of idiopathic
epilepsy was more frequently diagnosed, than in cases with complete diagnostic
work-up. Concerning the confirmed diagnoses altogether 145 dogs had a
neurological examination as well as a MRI examination. In these cases kappa-index
was calculated and a slight correlation exists concerning the result of the neurological
examination and the result of MRI (kappa-index 0.1358). Supposed postictal changes
could be found in the MRI-sequences of 10 patients. A correlation whether postictal
changes are associated with normal or abnormal MRI results could not be
established (kappa-index -0.0640) as well as a correlation between the occurrence of
postictal changes and the period between last seizure and MRI (p=0.1911). The
performance of imaging techniques such as CT and MRI seems to enhance the
diagnosis of symptomatic epilepsy and is recommended in patients suffering from
seizures, especially at an age over 6 years. Postictal changes are a rare finding and
occur mostly when the time between MRI performance and last seizure event is
under four days.
Summary 43
In 30% of epileptic dogs, treatment with Phenobarbital (PB) and/or potassium
bromide (KBr) does not result in adequate seizure control. Modulation of efflux of p-
glycoprotein function may therefore help to overcome drug-refractoriness.
In the present study we tested whether add-on treatment with the P-glycoprotein
modulator Verapamil restores PB efficacy in patients with refractory epilepsy. The
study was divided into two parts: a) in six healthy beagle dogs side effects and
compatibility of these drugs as well as the influence on plasma and cerebrospinal
fluid (CSF) levels of PB was investigated; b) in eleven dogs with refractory epilepsy,
which were considered to be non-responders to PB, add-on treatment with Verapamil
(1 mg/kg bwt twice daily) was tested. In those patients in which no improvement of
seizure control could be achieved, Verapamil was discontinued and Levetiracetam
was applied as add-on medication.
In healthy beagle dogs no side-effects regarding clinical and neurological
examination, blood pressure and blood examination could be observed except for
one dog which developed bradycardia. PB levels in CSF did not increase after add-
on treatment with Verapamil. In the second part of the study clinical and neurological
examination, blood cell count and serum chemistry, measurement of blood pressure
and ECG were performed at the time point of inclusion in the study and during control
examinations every four weeks for four months in all patients.
In five of the eleven dogs add-on treatment was discontinued before the end of the
four-month period because of either severe cluster seizures or lack of an
improvement in seizure control. From the remaining six patients only one dog
responded with a 75% reduction in seizure frequency. One of the eleven patients
developed severe bradycardia. No further side effects were seen.
Following discontinuation of Verapamil eight of the non-responders received add-on
treatment with Levetiracetam (10-20 mg/kg bwt three times daily) for three to eight
months. Three of these dogs could be classified as responders.
This prospective study may indicate that the P-glycoprotein inhibitor Verapamil is not
appropriate for preventing pathological efflux of PB in dogs at the dosage used.
Levetiracetam proved to be a useful add-on medication in a subpopulation of PB
non-responders.
44 Zusammenfassung
8 Zusammenfassung
Jambroszyk, Melanie:
Studien zur Epilepsie des Hundes: Von der Diagnosestellung mit neuen
bildgebenden Verfahren bis zur innovativen Behandlungsstrategie
In einer Hundepopulation mit neurologischen Krankheiten treten bei etwa 10% der
Tiere Krampfanfälle auf. Frühere Studien zeigen, dass die Inzidenz der
symptomatischen Epilepsie, welche durch Gehirntumore, entzündliche
Gehirnerkrankungen und Missbildungen verursacht wird, genauso hoch ist wie in der
Humanmedizin. Deswegen sollte die Magnetresonanztomographie (MRT) als
Routineuntersuchung in der Veterinärmedizin ebenso wie in der Humanmedizin
eingesetzt werden. Zusätzlich zu den zahlreichen Gehirnläsionen sind postiktale
Veränderungen beschrieben. Diese sind durch in T2-gewichteten Sequenzen
hyperintense Bereiche gekennzeichnet, wobei nur ein geringgradiger Masseneffekt
zu sehen ist. Diese postiktalen Veränderungen treten vor allem bei Patienten auf,
welche unter generalisierten Krampfanfällen leiden, wobei sie bei
Kontrolluntersuchungen mittels MRT nicht mehr existieren.
Das Ziel dieses retrospektiven Teils der Untersuchung war, das aktuelle Verhältnis
zwischen idiopathischer und symptomatischer Epilepsie zu evaluieren. Hierfür
wurden 343 Patienten in die Untersuchungen mit einbezogen, welche aufgrund von
Krampfanfällen in der Klinik für Kleintiere der Tierärztlichen Hochschule Hannover
nach Einführung der Magnetresonanztomographie vorgestellt wurden.
Mittels Chi-Quadrat-Test konnte eine signifikant unterschiedliche Verteilung der
Patienten hinsichtlich des ätiologischen Ursprungs errechnet werden (p=0,0005). In
der Gruppe der Hunde, bei denen nach klinisch-neurologischer Untersuchung und
Abklärung von Stoffwechselerkrankungen nur eine Verdachtsdiagnose gestellt
werden konnte, wurde die Diagnose der idiopathischen Epilepsie signifikant häufiger
gestellt als bei den Tieren bei denen eine komplette diagnostische Aufarbeitung mit
modernen bildgebenden Verfahren durchgeführt wurde.
Zusammenfassung 45
In der Gruppe der gesicherten Diagnosen wurden bei 145 Hunden sowohl eine
neurologische Untersuchung als auch eine MRT durchgeführt. In diesen Fällen
wurde der Kappa-Index errechnet und eine leichte Korrelation zwischen dem
Resultat der neurologischen Untersuchung und dem Ergebnis der MRT bestätigt
(Kappa-Index 0,1358). Vermutete postiktale Veränderungen wurden in den MRT-
Sequenzen von 10 Patienten gefunden. Eine Korrelation, dass postiktale
Veränderungen mit einem pathologischen Befund in der MRT zusammenhängen,
konnte nicht bewiesen werden (Kappa-Index -0,0640). Dieses gilt auch für einen
Zusammenhang zwischen dem Auftreten von postiktalen Veränderungen und dem
Zeitraum zwischen dem letzten Krampfanfall und der Untersuchung mittels MRT
(p=0,1911). Eine Tendenz war zu erkennen, dass postiktale Veränderungen
vermehrt auftreten, wenn die MRT in den ersten vier Tagen nach dem letzten
Krampfanfall durchgeführt wurde.
Bei ungefähr 30% der Hunde, die unter Krampfanfällen leiden, bringt eine Therapie
mit Phenobarbital und/oder Kaliumbromid keine ausreichende Kontrolle der
Anfallsfrequenz. Eine Modulation der Funktion von P-Glycoprotein-Rezeptoren
könnte gegebenenfalls einen Beitrag dazu leisten, dass der lokale Spiegel wirksamer
Antiepileptika im Gehirn erhöht wird. In diesem prospektiven Teil der Studie wurde
getestet, ob eine Kombinationstherapie des P-Glykoprotein-Modulators Verapamil
die Effektivität der Behandlung mit Phenobarbital bei Patienten mit
Pharmakoresistenz wieder herstellt.
Diese Studie wurde in zwei Teile gegliedert. In der Vorstudie wurden sechs gesunde
Beagle mit Phenobarbital und Verapamil behandelt und Verträglichkeit,
Nebenwirkungen und die Beeinflussung des Phenobarbitalspiegels in Serum und
Liquor cerebrospinalis dokumentiert. In dieser Vorstudie konnten keine
Nebenwirkungen in Bezug auf klinische und neurologische Untersuchung, Blutdruck-
Kontrolle und Blutuntersuchung festgestellt werden. Lediglich ein Hund entwickelte
eine Bradykardie. Der Phenobarbitalspiegel im Liquor cerebrospinalis stieg jedoch
nicht an, nachdem Verapamil zusätzlich verabreicht wurde. Zum anderen wurden in
die Hauptstudie 11 Patienten mit refraktärer Epilepsie aufgenommen. Diese
Patienten reagierten nicht adäquat auf die Behandlung mit Phenobarbital allein, so
46 Zusammenfassung
dass eine Kombinationstherapie mit Verapamil (1mg/kg zweimal täglich) eingeleitet
wurde. Bei den Patienten bei denen dadurch kein positiver Effekt vermerkt werden
konnte, wurde Verapamil abgesetzt und eine Kombinationstherapie mit
Phenobarbital und Levetiracetam durchgeführt. In der Hauptstudie wurde jeweils eine
klinische Allgemeinuntersuchung, eine neurologische Untersuchung, eine
Blutuntersuchung, Messung von Blutdruck und ein EKG bei Eintritt in die Studie und
anschließend alle vier Wochen bei allen elf Patienten durchgeführt. Bei fünf der elf
Patienten konnte die Behandlung mit Phenobarbital und Verapamil nicht weiter
durchgeführt werden, da entweder schwere Clusteranfälle auftraten oder keine
Verbesserung der Anfallsfrequenz erreicht werden konnte. Von den verbleibenden
sechs Patienten sprach mit einer 75%igen Reduktion der Anfallsfrequenz lediglich
einer ausreichend auf diese Therapie an und konnte somit als Responder betrachtet
werden. Ein weiterer dieser elf Patienten entwickelte eine sehr schwere Bradykardie.
Wurde Verapamil aufgrund von Nebenwirkungen oder fehlendem Erfolg abgesetzt,
so folgte eine Behandlung mit Phenobarbital und Levetiracetam (10-20mg/kg dreimal
täglich) über vier bis acht Monate (8 Hunde). Drei dieser 8 Hunde konnten als
Levetiracetam-Responder klassifiziert werden.
Der Teil dieser Studie, der sich mit neuen Behandlungsstrategien beschäftigt hat,
deutet an, dass der P-Glykoprotein-Inhibitor Verapamil in der hier verwendeten
Dosierung nicht angemessen dazu beiträgt, die Frequenz der Krampfanfälle zu
reduzieren. Levetiracetam scheint ein geeignetes Medikament zu sein um einen Teil
der Hund mit pharmakoresistenter Epilepsie erfolgreich behandeln zu können.
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58 Appendix
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.3.2
004
4761
13,0
4ge
nera
l12
zwei
wun
auffä
llig
211
SO
NS
TM
K1.
1.19
996.
4.20
0418
955,
19ge
nera
l1
tgl
unau
ffälli
g22
2T
EC
KE
LM
28.1
.199
56.
4.20
0433
089,
06ko
mpl
.9
wöc
hent
lun
auffä
llig
231
BC
M6.
6.20
0211
.4.2
004
665
1,82
gene
ral
2m
onat
lun
auffä
llig
241
LRM
9.4.
2002
12.4
.200
472
31,
98ge
nera
l2
erst
mal
sun
auffä
llig
251
SO
NS
TW
30.5
.200
113
.4.2
004
1033
2,83
gene
ral
3er
stm
als
unau
ffälli
g26
2S
ON
ST
MK
18.7
.200
113
.4.2
004
985
2,70
gene
ral
1m
onat
lun
auffä
llig
271
MIX
M12
.7.2
001
15.4
.200
499
32,
72ge
nera
l2,
5m
onat
lun
auffä
llig
281
BC
MK
12.6
.200
220
.4.2
004
668
1,83
gene
ral
1,5
unau
ffälli
g29
1S
ON
ST
M15
.7.1
996
25.4
.200
428
007,
67ge
nera
l8
erst
mal
sun
auffä
llig
301
MÜ
NS
TW
1.1.
1999
26.4
.200
419
155,
25ge
nera
l5
mon
atl
unau
ffälli
g31
2M
IXM
30.7
.199
63.
5.20
0427
937,
65ge
nera
l7
wöc
hent
lun
auffä
llig
321
SO
NS
TM
11.1
1.19
964.
5.20
0426
937,
38ge
nera
l4
zwei
wun
auffä
llig
331
SC
HM
1.1.
2001
5.5.
2004
1204
3,30
gene
ral
3er
stm
als
unau
ffälli
g34
1M
IXM
1.9.
1993
8.5.
2004
3847
10,5
4ge
nera
l11
erst
mal
sun
auffä
llig
352
SO
NS
TM
23.5
.200
310
.5.2
004
347
0,95
foka
l/kom
plex
1w
öche
ntl
abno
rmal
361
HU
SK
YW
4.11
.200
010
.5.2
004
1266
3,47
gene
ral
4tg
lun
auffä
llig
371
BE
AG
LEM
3.3.
2000
11.5
.200
415
084,
13ge
nera
lun
auffä
llig
381
SO
NS
TM
10.1
1.20
0311
.5.2
004
181
0,50
gene
ral
0,5
wöc
hent
lun
auffä
llig
391
CO
CK
ER
MK
1.7.
1998
13.5
.200
421
125,
79ge
nera
l1
mon
atl
unau
ffälli
g40
2S
ON
ST
M15
.7.2
001
14.5
.200
410
192,
79ge
nera
l3
mon
atl
unau
ffälli
g
Appendix 59
Nr.
Labo
rne
uro
usm
rtD
atum
mrt
letz
ter
anfa
llm
rt D
iagn
ose
post
ikt.
Ver
änd.
Zel
len
liquo
rS
tatu
s ep
il.cl
uste
rE
nddi
agno
seE
utha
nasi
e1
unau
ffälli
gun
auffä
llig
nich
t pos
tikta
l19
.2.2
004
5.2.
2004
idio
path
isch
nein
0ne
inne
inid
iopa
this
chne
in2
unau
ffälli
gun
auffä
llig
post
ikta
l25
.3.2
004
24.3
.200
4id
iopa
this
chne
in1
nein
jaid
iopa
this
chja
3un
auffä
llig
unau
ffälli
g3.
3.20
04id
iopa
this
chne
in1
nein
jaid
iopa
this
chne
in4
unau
ffälli
gun
auffä
llig
post
ikta
l5.
3.20
043.
3.20
04id
iopa
this
chne
in0
nein
jaid
iopa
this
chne
in5
unau
ffälli
gun
auffä
llig
nich
t pos
tikta
l12
.3.2
004
7.3.
2004
idio
path
isch
nein
1ne
inja
idio
path
isch
nein
6un
auffä
llig
unau
ffälli
gne
inja
met
.-to
x.ne
in7
unau
ffälli
gun
auffä
llig
post
ikta
l12
.3.2
004
11.3
.200
4A
nom
alie
nein
0ne
inja
Ano
mal
ieja
8un
auffä
llig
post
ikta
l15
.3.2
004
12.3
.200
4ne
opla
stis
chne
in0
jane
inne
opla
stis
chja
9un
auffä
llig
unau
ffälli
gne
inne
inid
iopa
this
chne
in10
unau
ffälli
gun
auffä
llig
nein
jaid
iopa
this
chne
in11
unau
ffälli
gun
auffä
llig
3.6.
2004
2.5.
2004
idio
path
isch
nein
0ne
inne
inm
et.-
tox.
nein
12un
auffä
llig
unau
ffälli
gne
inja
idio
path
isch
nein
13un
auffä
llig
unau
ffälli
gne
inne
inid
iopa
this
chne
in14
unau
ffälli
gun
auffä
llig
nich
t pos
tikta
l31
.3.2
004
15.3
.200
4id
iopa
this
chne
in1
nein
nein
idio
path
isch
nein
15ab
norm
alne
inja
Ano
mal
ieja
16ab
norm
alab
norm
alpo
stik
tal
2.4.
2004
30.3
.200
4id
iopa
this
chne
in6
jane
inde
gene
rativ
ja17
unau
ffälli
gne
inja
entz
ündl
ich
nein
18un
auffä
llig
unau
ffälli
g7.
4.20
04id
iopa
this
chne
in0
nein
nein
idio
path
isch
nein
19un
auffä
llig
unau
ffälli
gne
inne
inid
iopa
this
chne
in20
abno
rmal
post
ikta
l6.
4.20
043.
4.20
04id
iopa
this
chne
in0
nein
jam
et.-
tox.
vers
torb
en21
unau
ffälli
gun
auffä
llig
nich
t pos
tikta
l6.
4.20
0430
.3.2
004
idio
path
isch
nein
0ne
inja
idio
path
isch
nein
22un
auffä
llig
unau
ffälli
gne
inja
idio
path
isch
nein
23un
auffä
llig
unau
ffälli
gpo
stik
tal
14.4
.200
411
.4.2
004
idio
path
isch
nein
1ne
inja
idio
path
isch
nein
24un
auffä
llig
abno
rmal
jane
inm
et.-
tox.
nein
25un
auffä
llig
unau
ffälli
gpo
stik
tal
16.4
.200
413
.4.2
004
vask
ulär
nein
0ne
inja
vask
ulär
nein
26un
auffä
llig
abno
rmal
nein
jam
et.-
tox.
nein
27un
auffä
llig
unau
ffälli
g15
.4.2
004
idio
path
isch
nein
0ne
inja
idio
path
isch
nein
28ab
norm
alun
auffä
llig
12.5
.200
4id
iopa
this
chne
in0
nein
jaid
iopa
this
chne
in29
unau
ffälli
gun
auffä
llig
post
ikta
l26
.4.2
004
25.4
.200
4id
iopa
this
chne
in0
nein
jam
et.-
tox.
nein
30un
auffä
llig
abno
rmal
post
ikta
l27
.4.2
004
25.4
.200
4id
iopa
this
chne
in1
nein
jaid
iopa
this
chja
31un
auffä
llig
unau
ffälli
gne
inja
met
.-to
x.ne
in32
unau
ffälli
gun
auffä
llig
29.8
.200
3id
iopa
this
chne
in1
nein
jaid
iopa
this
chne
in33
abno
rmal
abno
rmal
jane
inid
iopa
this
chja
34ab
norm
alun
auffä
llig
post
ikta
l17
.5.2
004
16.5
.200
4ne
opla
stis
chne
in0
nein
jane
opla
stis
chne
in35
unau
ffälli
gun
auffä
llig
nein
jaid
iopa
this
chne
in36
unau
ffälli
gun
auffä
llig
post
ikta
l10
.5.2
004
10.5
.200
4id
iopa
this
chne
in1
nein
jaid
iopa
this
chne
in37
unau
ffälli
gun
auffä
llig
11.5
.200
4id
iopa
this
chne
in1
nein
nein
idio
path
isch
nein
38un
auffä
llig
unau
ffälli
gpo
stik
tal
24.5
.200
423
.5.2
004
idio
path
isch
nein
0ne
inja
idio
path
isch
nein
39ab
norm
alab
norm
alpo
stik
tal
13.5
.200
413
.5.2
004
idio
path
isch
nein
0ne
inja
idio
path
isch
nein
40un
auffä
llig
unau
ffälli
gne
inne
inid
iopa
this
chne
in
60 Appendix
Nr.
Gru
ppe
Ras
seG
esch
lech
tG
ebur
tsd.
Vor
stel
lung
sdV
orst
ella
lter
dV
orst
ella
lter
yP
robl
emat
ikA
uftr
ittsa
lter
yF
requ
enz
allg
us
412
GR
MK
18.7
.200
117
.5.2
004
1019
2,79
gene
ral
2w
öche
ntl
unau
ffälli
g42
1D
SH
W23
.4.2
003
25.5
.200
439
21,
07ge
nera
l1
mon
atl
unau
ffälli
g43
1Y
OR
KW
9.4.
2002
27.5
.200
476
82,
10ge
nera
l/kom
plex
2er
stm
als
unau
ffälli
g44
2B
CW
21.1
.200
431
.5.2
004
130
0,36
gene
ral
0,25
erst
mal
sun
auffä
llig
452
MIX
M1.
1.19
981.
6.20
0423
106,
33ge
nera
l6
erst
mal
sun
auffä
llig
462
MIX
WK
15.1
2.20
001.
6.20
0412
463,
41fo
kal
2,5
mon
atl
unau
ffälli
g47
2JR
TM
31.8
.199
84.
6.20
0420
745,
68ge
nera
l6
erst
mal
sab
norm
al48
1D
SH
W25
.5.1
998
6.6.
2004
2171
5,95
gene
ral
6tg
lun
auffä
llig
491
TE
CK
EL
W28
.4.2
001
7.6.
2004
1119
3,07
gene
ral
2m
onat
lun
auffä
llig
501
SC
HW
K1.
10.2
002
7.6.
2004
606
1,66
gene
ral
2er
stm
als
unau
ffälli
g51
2S
ON
ST
M12
.8.2
003
8.6.
2004
296
0,81
kom
pl.
0,5
erst
mal
sun
auffä
llig
521
JRT
W1.
1.19
9910
.6.2
004
1959
5,37
gene
ral
5er
stm
als
abno
rmal
532
HU
SK
YW
25.1
1.19
9810
.6.2
004
1995
5,47
gene
ral
6er
stm
als
abno
rmal
541
MIX
WK
1.1.
1994
19.6
.200
437
6810
,32
gene
ral
10er
stm
als
unau
ffälli
g55
1JR
TM
K1.
1.19
9721
.6.2
004
2690
7,37
gene
ral
5un
auffä
llig
561
SO
NS
TW
26.6
.200
121
.6.2
004
1075
2,95
gene
ral/f
okal
4er
stm
als
unau
ffälli
g57
1B
RA
CK
EM
1.4.
2003
22.6
.200
611
613,
18ge
nera
l1
mon
atl
unau
ffälli
g58
1M
IXW
26.1
.200
429
.6.2
004
153
0,42
gene
ral
0,5
wöc
hent
lun
auffä
llig
592
SO
NS
TM
K23
.5.2
000
5.7.
2004
1482
4,06
foka
l3
mon
atl
unau
ffälli
g60
2S
ET
TE
RM
16.5
.200
16.
7.20
0411
303,
10ge
nera
l3
erst
mal
sun
auffä
llig
612
DS
HM
20.1
1.19
966.
7.20
0427
467,
52ge
nera
l6,
5jä
hrl
unau
ffälli
g62
2M
IXW
K1.
1.19
9612
.7.2
004
3071
8,41
gene
ral
7jä
hrl
unau
ffälli
g63
1S
ON
ST
MK
1.6.
2002
19.7
.200
476
82,
10ge
nera
l2
zwei
wun
auffä
llig
641
LRM
K1.
3.20
0227
.7.2
004
866
2,37
gene
ral
2m
onat
lun
auffä
llig
652
MIX
M24
.2.1
993
28.7
.200
441
1411
,27
foka
l11
tgl
unau
ffälli
g66
1H
US
KY
WK
27.1
0.19
9528
.7.2
004
3151
8,63
gene
ral
9er
stm
als
unau
ffälli
g67
1S
ON
ST
M28
.7.1
998
29.7
.200
421
615,
92ge
nera
l6
erst
mal
sun
auffä
llig
682
SO
NS
TM
20.7
.200
12.
8.20
0410
922,
99ge
nera
l3
erst
mal
sun
auffä
llig
692
LRW
K19
.4.2
000
2.8.
2004
1543
4,23
foka
l4
erst
mal
sun
auffä
llig
702
SO
NS
TM
1.9.
2003
2.8.
2004
331
0,91
foka
l1
mon
atl
unau
ffälli
g71
2S
ON
ST
WK
1.1.
2000
2.8.
2004
1651
4,52
foka
l4,
5er
stm
als
unau
ffälli
g72
2S
ON
ST
WK
1.4.
2000
2.8.
2004
1561
4,28
gene
ral
4er
stm
als
unau
ffälli
g73
2S
ON
ST
MK
12.6
.199
93.
8.20
0418
515,
07ge
nera
l5
erst
mal
sun
auffä
llig
741
MIX
WK
4.4.
1998
9.8.
2004
2285
6,26
gene
ral
6er
stm
als
unau
ffälli
g75
1H
US
KY
W1.
6.20
0110
.8.2
004
1149
3,15
gene
ral
3er
stm
als
unau
ffälli
g76
2B
OX
ER
W1.
1.20
0316
.8.2
004
585
1,60
gene
ral
1,5
erst
mal
sun
auffä
llig
771
DS
HM
1.9.
1999
18.8
.200
417
874,
90ge
nera
l3
mon
atl
unau
ffälli
g78
2G
RW
1.11
.200
223
.8.2
004
652
1,79
gene
ral
2m
onat
lun
auffä
llig
791
GR
MK
7.3.
2002
23.8
.200
488
62,
43ge
nera
l2,
5w
öche
ntl
unau
ffälli
g80
2JR
TW
K1.
1.19
9923
.8.2
004
2032
5,57
gene
ral
5er
stm
als
unau
ffälli
g
Appendix 61
Nr.
Labo
rne
uro
usm
rtD
atum
mrt
letz
ter
anfa
llm
rt D
iagn
ose
post
ikt.
Ver
änd.
Zel
len
liquo
rS
tatu
s ep
il.cl
uste
rE
nddi
agno
seE
utha
nasi
e41
abno
rmal
unau
ffälli
gne
inne
inid
iopa
this
chne
in42
unau
ffälli
gun
auffä
llig
post
ikta
l2.
6.20
0431
.5.2
004
idio
path
isch
nein
0ne
inja
idio
path
isch
nein
43ab
norm
alpo
stik
tal
28.5
.200
427
.5.2
004
idio
path
isch
nein
0ne
inne
inid
iopa
this
chne
in44
abno
rmal
jane
inm
et.-
tox.
nein
45un
auffä
llig
unau
ffälli
gne
inne
inid
iopa
this
chne
in46
unau
ffälli
gun
auffä
llig
nein
nein
idio
path
isch
nein
47un
auffä
llig
nein
nein
met
.-to
x.ne
in48
unau
ffälli
gun
auffä
llig
post
ikta
l7.
6.20
046.
6.20
04ne
opla
stis
chne
in0
nein
jane
opla
stis
chne
in49
unau
ffälli
gun
auffä
llig
8.2.
2005
idio
path
isch
nein
2ne
inne
inid
iopa
this
chne
in50
unau
ffälli
gun
auffä
llig
post
ikta
l9.
6.20
047.
6.20
04id
iopa
this
chne
in0
nein
jaid
iopa
this
chja
51ab
norm
alun
auffä
llig
nein
nein
idio
path
isch
nein
52ab
norm
alab
norm
alni
cht p
ostik
tal
10.6
.200
431
.5.2
004
neop
last
isch
nein
220
nein
nein
neop
last
isch
ja53
abno
rmal
jaja
met
.-to
x.ne
in54
unau
ffälli
gun
auffä
llig
post
ikta
l30
.6.2
004
29.6
.200
4id
iopa
this
chne
in0
nein
nein
idio
path
isch
nein
55un
auffä
llig
abno
rmal
nich
t pos
tikta
l22
.6.2
004
2.6.
2004
idio
path
isch
nein
3ne
inne
inid
iopa
this
chne
in56
abno
rmal
abno
rmal
nein
nein
met
.-to
x.ne
in57
unau
ffälli
gun
auffä
llig
post
ikta
l24
.6.2
004
21.6
.200
4id
iopa
this
chne
in0
nein
jaid
iopa
this
chne
in58
abno
rmal
abno
rmal
post
ikta
l29
.6.2
004
27.6
.200
4en
tzün
dlic
hne
in0
nein
jaen
tzün
dlic
hne
in59
abno
rmal
unau
ffälli
gne
inne
inid
iopa
this
chne
in60
unau
ffälli
gun
auffä
llig
nein
nein
idio
path
isch
nein
61un
auffä
llig
unau
ffälli
gne
inne
inid
iopa
this
chne
in62
abno
rmal
unau
ffälli
gne
inne
inid
iopa
this
chne
in63
unau
ffälli
gun
auffä
llig
28.7
.200
4en
tzün
dlic
hne
in0
nein
jaen
tzün
dlic
hne
in64
unau
ffälli
gun
auffä
llig
nein
nein
idio
path
isch
nein
65un
auffä
llig
nein
nein
met
.-to
x.ne
in66
abno
rmal
unau
ffälli
gni
cht p
ostik
tal
9.8.
2004
4.8.
2004
entz
ündl
ich
nein
1ne
inja
dege
nera
tivne
in67
abno
rmal
abno
rmal
nich
t pos
tikta
l29
.7.2
004
23.7
.200
4ne
opla
stis
chne
in0
nein
jane
opla
stis
chja
68ab
norm
alab
norm
alja
nein
idio
path
isch
ja69
abno
rmal
unau
ffälli
gne
inne
inm
et.-
tox.
nein
70un
auffä
llig
unau
ffälli
gne
inne
inid
iopa
this
chne
in71
unau
ffälli
gun
auffä
llig
nein
nein
met
.-to
x.ne
in72
unau
ffälli
gun
auffä
llig
nein
jam
et.-
tox.
nein
73un
auffä
llig
nein
nein
met
.-to
x.ne
in74
abno
rmal
unau
ffälli
gne
inne
inm
et.-
tox.
nein
75un
auffä
llig
abno
rmal
post
ikta
l11
.9.2
004
9.8.
2004
idio
path
isch
nein
0ne
inne
inid
iopa
this
chne
in76
unau
ffälli
gun
auffä
llig
nein
nein
idio
path
isch
nein
77un
auffä
llig
unau
ffälli
gni
cht p
ostik
tal
18.8
.200
412
.8.2
004
idio
path
isch
nein
1ne
inja
idio
path
isch
nein
78un
auffä
llig
unau
ffälli
gne
inne
inid
iopa
this
chne
in79
unau
ffälli
gun
auffä
llig
post
ikta
l5.
10.2
004
3.10
.200
4id
iopa
this
chne
in1
nein
jaid
iopa
this
chne
in80
unau
ffälli
gab
norm
alne
inne
inid
iopa
this
chne
in
62 Appendix
Nr.
Gru
ppe
Ras
seG
esch
lech
tG
ebur
tsd.
Vor
stel
lung
sdV
orst
ella
lter
dV
orst
ella
lter
yP
robl
emat
ikA
uftr
ittsa
lter
yF
requ
enz
allg
us
811
DS
HM
19.4
.200
324
.8.2
004
485
1,33
gene
ral
0,2
mon
atl
unau
ffälli
g82
1S
ON
ST
W10
.2.2
001
24.8
.200
412
743,
49ge
nera
l2
mon
atl
unau
ffälli
g83
2R
OT
TM
1.5.
1999
26.8
.200
419
155,
25ge
nera
l5
wöc
hent
lun
auffä
llig
842
PU
DE
LM
1.1.
1991
1.9.
2004
4920
13,4
8ge
nera
l13
erst
mal
sun
auffä
llig
851
WH
WT
MK
12.8
.199
66.
9.20
0429
047,
96ge
nera
l5
vier
telj
unau
ffälli
g86
2S
CH
M1.
1.19
946.
9.20
0438
4510
,53
gene
ral
8un
auffä
llig
871
MIX
W1.
1.19
998.
9.20
0420
475,
61ge
nera
l/fok
al5,
5er
stm
als
unau
ffälli
g88
2Y
OR
KM
1.11
.199
113
.9.2
004
4632
12,6
9ge
nera
l13
erst
mal
sun
auffä
llig
892
BE
AG
LEW
15.4
.200
414
.9.2
004
149
0,41
gene
ral
0,5
erst
mal
sun
auffä
llig
902
CO
CK
ER
WK
6.6.
1996
25.9
.200
429
898,
19ge
nera
l7
vier
telj
unau
ffälli
g91
1B
OX
ER
M1.
1.20
0125
.9.2
004
1344
3,68
gene
ral
3,5
mon
atl
unau
ffälli
g92
2S
ON
ST
W6.
2.20
0127
.9.2
004
1311
3,59
gene
ral
2,5
wöc
hent
lun
auffä
llig
931
BC
WK
13.8
.199
628
.9.2
004
2925
8,01
gene
ral
5w
öche
ntl
unau
ffälli
g94
2S
ON
ST
M7.
8.19
951.
10.2
004
3294
9,02
gene
ral
9er
stm
als
unau
ffälli
g95
2C
OC
KE
RW
1.1.
2000
4.10
.200
417
134,
69ge
nera
l3,
5vi
erte
ljun
auffä
llig
962
MIX
M1.
1.19
985.
10.2
004
2434
6,67
gene
ral
5,5
wöc
hent
lun
auffä
llig
972
MÜ
NS
TM
1.3.
2003
11.1
0.20
0458
01,
59ge
nera
l0,
75un
auffä
llig
981
LRM
K24
.12.
2002
28.9
.200
463
41,
74ge
nera
l1,
5zw
eiw
unau
ffälli
g99
1P
UD
EL
WK
10.1
2.19
9712
.10.
2004
2462
6,75
gene
ral/f
okal
3vi
erte
ljun
auffä
llig
100
1M
IXW
25.1
0.20
0014
.10.
2004
1429
3,92
gene
ral
4vi
erte
ljun
auffä
llig
101
1JR
TM
K20
.10.
1999
15.1
0.20
0417
954,
92ge
nera
l1,
5vi
erte
ljun
auffä
llig
102
1M
IXM
1.5.
1999
25.1
0.20
0419
745,
41ge
nera
l3
vier
telj
unau
ffälli
g10
31
SO
NS
TW
K29
.9.1
999
7.11
.200
418
385,
04ge
nera
l5
erst
mal
sun
auffä
llig
104
2B
CM
15.1
.200
09.
11.2
004
1734
4,75
gene
ral
2vi
erte
ljun
auffä
llig
105
2S
ET
TE
RM
12.6
.199
711
.11.
2004
2669
7,31
gene
ral
7,5
erst
mal
sun
auffä
llig
106
1B
OX
ER
M7.
5.20
0319
.11.
2004
552
1,51
gene
ral
1,5
zwei
wab
norm
al10
72
YO
RK
WK
3.1.
1995
22.1
1.20
0435
599,
75ge
nera
l9,
5m
onat
lun
auffä
llig
108
1W
HW
TW
K1.
5.19
9423
.11.
2004
3802
10,4
2ge
nera
l10
erst
mal
sun
auffä
llig
109
2LR
MK
1.10
.199
923
.11.
2004
1852
5,07
gene
ral
2zw
eiw
unau
ffälli
g11
02
SO
NS
TW
K3.
4.19
9525
.11.
2004
3472
9,51
gene
ral
9ha
lbj
unau
ffälli
g11
11
BE
AG
LEM
25.3
.200
126
.11.
2004
1321
3,62
gene
ral
2vi
erte
ljun
auffä
llig
112
1D
SH
M27
.10.
2002
29.1
1.20
0475
22,
06ge
nera
l2
wöc
hent
lun
auffä
llig
113
2T
EC
KE
LW
27.4
.200
130
.11.
2004
1293
3,54
gene
ral
3,5
mon
atl
unau
ffälli
g11
42
SO
NS
TM
17.7
.200
37.
12.2
004
500
1,37
gene
ral
1,5
zwei
wun
auffä
llig
115
2M
IXM
14.1
1.19
967.
12.2
004
2903
7,95
gene
ral
8zw
eiw
unau
ffälli
g11
61
LRW
6.2.
2004
7.12
.200
430
10,
82ge
nera
l0,
75er
stm
als
unau
ffälli
g11
72
SO
NS
TM
5.11
.200
214
.12.
2004
759
2,08
gene
ral
1,5
vier
telj
unau
ffälli
g11
81
SO
NS
TM
8.4.
2003
15.1
2.20
0460
71,
66ge
nera
l1,
5m
onat
lun
auffä
llig
119
2S
ON
ST
M23
.6.1
999
16.1
2.20
0419
735,
41ge
nera
l5,
5er
stm
als
unau
ffälli
g12
01
SO
NS
TW
15.1
0.19
9424
.12.
2004
3669
10,0
5ge
nera
l6
mon
atl
unau
ffälli
g
Appendix 63
Nr.
Labo
rne
uro
usm
rtD
atum
mrt
letz
ter
anfa
llm
rt D
iagn
ose
post
ikt.
Ver
änd.
Zel
len
liquo
rS
tatu
s ep
il.cl
uste
rE
nddi
agno
seE
utha
nasi
e81
unau
ffälli
gab
norm
alpo
stik
tal
24.8
.200
423
.8.2
004
idio
path
isch
nein
0ne
inja
idio
path
isch
nein
82un
auffä
llig
unau
ffälli
gni
cht p
ostik
tal
26.8
.200
42.
8.20
04A
nom
alie
nein
nein
nein
Ano
mal
iene
in83
unau
ffälli
gun
auffä
llig
nein
jane
opla
stis
chne
in84
abno
rmal
abno
rmal
nein
nein
neop
last
isch
ja85
abno
rmal
abno
rmal
nein
jam
et.-
tox.
nein
86un
auffä
llig
unau
ffälli
gne
inne
inid
iopa
this
chne
in87
abno
rmal
abno
rmal
nich
t pos
tikta
l10
.9.2
004
6.9.
2004
entz
ündl
ich
ja0
nein
nein
entz
ündl
ich
nein
88un
auffä
llig
abno
rmal
nein
nein
neop
last
isch
nein
89ab
norm
alun
auffä
llig
nein
nein
idio
path
isch
nein
90un
auffä
llig
abno
rmal
nein
jaid
iopa
this
chne
in91
unau
ffälli
gab
norm
alpo
stik
tal
27.4
.200
424
.9.2
004
idio
path
isch
nein
1ne
inja
idio
path
isch
nein
92ab
norm
alun
auffä
llig
nein
jaid
iopa
this
chne
in93
unau
ffälli
gun
auffä
llig
post
ikta
l29
.9.2
004
26.9
.200
4id
iopa
this
chne
in0
nein
jaid
iopa
this
chne
in94
unau
ffälli
gun
auffä
llig
nein
nein
idio
path
isch
nein
95un
auffä
llig
unau
ffälli
gne
inne
inid
iopa
this
chne
in96
unau
ffälli
gun
auffä
llig
nein
jaid
iopa
this
chne
in97
abno
rmal
unau
ffälli
gne
inja
idio
path
isch
nein
98un
auffä
llig
unau
ffälli
g12
.10.
2004
idio
path
isch
nein
0ne
inne
inid
iopa
this
chne
in99
unau
ffälli
gab
norm
alpo
stik
tal
15.1
0.20
0412
.10.
2004
idio
path
isch
nein
1ne
inne
inid
iopa
this
chne
in10
0un
auffä
llig
abno
rmal
post
ikta
l3.
2.20
041.
2.20
05id
iopa
this
chne
in0
nein
jaid
iopa
this
chne
in10
1un
auffä
llig
unau
ffälli
g4.
11.2
004
idio
path
isch
nein
0ne
inja
idio
path
isch
nein
102
unau
ffälli
gun
auffä
llig
nein
jam
et.-
tox.
nein
103
unau
ffälli
gun
auffä
llig
nich
t pos
tikta
l8.
11.2
004
15.1
0.20
04ne
opla
stis
chne
in63
nein
nein
neop
last
isch
nein
104
abno
rmal
abno
rmal
nein
nein
idio
path
isch
nein
105
unau
ffälli
gun
auffä
llig
nein
nein
idio
path
isch
nein
106
unau
ffälli
gab
norm
alni
cht p
ostik
tal
23.1
1.20
0419
.11.
2004
idio
path
isch
ja24
jaja
entz
ündl
ich
ja10
7ab
norm
alab
norm
alne
inne
inm
et.-
tox.
nein
108
abno
rmal
jaja
met
.-to
x.ja
109
unau
ffälli
gab
norm
alne
inne
inid
iopa
this
chne
in11
0un
auffä
llig
abno
rmal
nein
nein
entz
ündl
ich
nein
111
unau
ffälli
gun
auffä
llig
nein
jaid
iopa
this
chne
in11
2un
auffä
llig
abno
rmal
nich
t pos
tikta
l14
.12.
2004
9.12
.200
4id
iopa
this
chne
in1
nein
jane
opla
stis
chja
113
unau
ffälli
gun
auffä
llig
nein
jaid
iopa
this
chne
in11
4un
auffä
llig
unau
ffälli
gne
inne
inid
iopa
this
chne
in11
5un
auffä
llig
unau
ffälli
gne
inja
idio
path
isch
nein
116
abno
rmal
unau
ffälli
gpo
stik
tal
9.12
.200
47.
12.2
004
vask
ulär
nein
1ne
inja
vask
ulär
nein
117
unau
ffälli
gun
auffä
llig
nein
nein
idio
path
isch
nein
118
unau
ffälli
gun
auffä
llig
26.4
.200
5id
iopa
this
chne
in1
nein
nein
idio
path
isch
nein
119
unau
ffälli
gab
norm
alne
inja
idio
path
isch
nein
120
unau
ffälli
gab
norm
alpo
stik
tal
24.1
2.20
0424
.12.
2004
idio
path
isch
nein
jane
inid
iopa
this
chne
in
64 Appendix
Nr.
Gru
ppe
Ras
seG
esch
lech
tG
ebur
tsd.
Vor
stel
lung
sdV
orst
ella
lter
dV
orst
ella
lter
yP
robl
emat
ikA
uftr
ittsa
lter
yF
requ
enz
allg
us
121
1H
US
KY
W1.
5.20
0426
.12.
2004
235
0,64
gene
ral
0,75
erst
mal
sun
auffä
llig
122
2S
ON
ST
W7.
5.20
004.
1.20
0516
774,
59ge
nera
l4,
5ha
lbj
unau
ffälli
g12
31
JRT
M1.
1.19
9811
.1.2
005
2530
6,93
gene
ral/f
okal
4m
onat
lun
auffä
llig
124
2T
EC
KE
LM
19.4
.199
811
.1.2
005
2422
6,64
gene
ral
4un
auffä
llig
125
1B
EA
GLE
M10
.5.1
990
12.1
.200
552
8214
,47
gene
ral
15,5
erst
mal
sab
norm
al12
61
TE
CK
EL
MK
28.6
.199
612
.1.2
005
3074
8,42
gene
ral
9er
stm
als
unau
ffälli
g12
72
MIX
W1.
5.20
0417
.1.2
005
256
0,70
gene
ral
1er
stm
als
abno
rmal
128
1B
OX
ER
WK
12.5
.199
419
.1.2
005
3847
10,5
4ge
nera
l11
erst
mal
sun
auffä
llig
129
1S
CH
WK
1.1.
1992
19.1
.200
546
9812
,87
gene
ral
13er
stm
als
unau
ffälli
g13
02
MIX
M1.
8.20
0420
.1.2
005
169
0,46
gene
ral
0,5
erst
mal
sun
auffä
llig
131
1R
OT
TW
1.4.
1998
24.1
.200
524
536,
72ge
nera
l6,
5er
stm
als
unau
ffälli
g13
21
JRT
MK
16.1
0.19
9725
.1.2
005
2619
7,18
gene
ral
7w
öche
ntl
unau
ffälli
g13
31
WH
WT
W21
.2.1
993
25.1
.200
542
9411
,76
gene
ral
11,5
wöc
hent
lab
norm
al13
41
CO
CK
ER
M14
.1.1
999
1.2.
2005
2177
5,96
gene
ral
6er
stm
als
unau
ffälli
g13
52
MIX
W10
.10.
2004
3.2.
2005
113
0,31
foka
l0,
3er
stm
als
unau
ffälli
g13
61
SO
NS
TM
23.7
.199
53.
2.20
0534
309,
40ge
nera
l10
wöc
hent
lun
auffä
llig
137
2Y
OR
KM
13.7
.199
67.
2.20
0530
848,
45ge
nera
l1,
5vi
erte
ljun
auffä
llig
138
1M
IXW
K8.
8.19
957.
2.20
0534
199,
37ge
nera
l9
zwei
wun
auffä
llig
139
1S
ON
ST
W1.
1.20
018.
2.20
0514
774,
05ge
nera
l4
wöc
hent
lun
auffä
llig
140
1M
ÜN
ST
M17
.11.
2001
8.2.
2005
1161
3,18
gene
ral
3m
onat
lun
auffä
llig
141
2B
EA
GLE
M10
.7.2
004
18.2
.200
521
80,
60ge
nera
l0,
75er
stm
als
unau
ffälli
g14
22
SO
NS
TM
1.6.
2002
28.2
.200
598
72,
70ge
nera
l2,
5vi
erte
ljun
auffä
llig
143
1M
IXM
1.10
.199
51.
3.20
0533
909,
29ge
nera
l9
erst
mal
sun
auffä
llig
144
1G
RM
27.1
1.20
046.
3.20
0599
0,27
gene
ral
0,25
erst
mal
sun
auffä
llig
145
1M
IXM
16.1
2.20
048.
3.20
0582
0,22
gene
ral
0,25
erst
mal
sun
auffä
llig
146
1S
CH
M1.
1.20
0121
.3.2
005
1520
4,16
gene
ral
4w
öche
ntl
unau
ffälli
g14
72
DS
HW
7.9.
2003
21.3
.200
555
41,
52ge
nera
l1,
5zw
eiw
unau
ffälli
g14
81
TE
CK
EL
M1.
6.19
9622
.3.2
005
3171
8,69
gene
ral
4m
onat
lab
norm
al14
91
DS
HM
30.9
.199
523
.3.2
005
3413
9,35
gene
ral
9,5
erst
mal
sab
norm
al15
01
GR
M29
.3.1
998
3.4.
2005
2524
6,92
gene
ral
4m
onat
lab
norm
al15
11
MIX
WK
1.6.
2003
5.4.
2005
664
1,82
gene
ral
1vi
erte
ljun
auffä
llig
152
1M
IXW
11.1
1.20
0211
.4.2
005
870
2,38
foka
l2,
5tg
lab
norm
al15
31
MIX
M1.
1.20
0012
.4.2
005
1901
5,21
gene
ral
5zw
eiw
unau
ffälli
g15
42
MIX
M1.
1.20
0112
.4.2
005
1541
4,22
gene
ral
3,5
mon
atl
unau
ffälli
g15
52
SO
NS
TW
1.1.
2003
13.4
.200
582
22,
25ge
nera
l2
mon
atl
unau
ffälli
g15
62
SO
NS
TM
27.1
2.20
0215
.4.2
005
828
2,27
gene
ral
2m
onat
lun
auffä
llig
157
1C
OC
KE
RW
K1.
6.19
9718
.4.2
005
2837
7,77
kom
pl.
8er
stm
als
unau
ffälli
g15
82
GR
WK
2.3.
1997
18.4
.200
529
268,
02ge
nera
l8,
5er
stm
als
unau
ffälli
g15
91
MIX
M1.
1.19
9918
.4.2
005
2267
6,21
gene
ral
5,5
vier
telj
unau
ffälli
g16
01
MIX
WK
1.3.
1996
25.4
.200
532
949,
02fo
kal
9w
öche
ntl
unau
ffälli
g
Appendix 65
Nr.
Labo
rne
uro
usm
rtD
atum
mrt
letz
ter
anfa
llm
rt D
iagn
ose
post
ikt.
Ver
änd.
Zel
len
liquo
rS
tatu
s ep
il.cl
uste
rE
nddi
agno
seE
utha
nasi
e12
1un
auffä
llig
abno
rmal
nein
nein
entz
ündl
ich
ja12
2ab
norm
alun
auffä
llig
nein
nein
idio
path
isch
nein
123
abno
rmal
unau
ffälli
gni
cht p
ostik
tal
11.1
.200
57.
1.20
05en
tzün
dlic
hne
in1
nein
jaen
tzün
dlic
hne
in12
4un
auffä
llig
unau
ffälli
gne
inne
inid
iopa
this
chne
in12
5ab
norm
alun
auffä
llig
nein
nein
met
.-to
x.ne
in12
6un
auffä
llig
unau
ffälli
gne
inja
idio
path
isch
nein
127
unau
ffälli
gab
norm
alne
inne
intr
aum
atis
chne
in12
8un
auffä
llig
abno
rmal
post
ikta
l19
.1.2
005
18.1
.200
5ne
opla
stis
chne
in1
nein
jane
opla
stis
chja
129
unau
ffälli
gun
auffä
llig
post
ikta
l20
.1.2
005
19.1
.200
5id
iopa
this
chja
5ne
inja
idio
path
isch
nein
130
unau
ffälli
gab
norm
alne
inja
idio
path
isch
nein
131
unau
ffälli
gun
auffä
llig
nein
nein
met
.-to
x.ne
in13
2ab
norm
alun
auffä
llig
nein
nein
met
.-to
x.ne
in13
3ab
norm
alun
auffä
llig
post
ikta
l28
.1.2
005
28.1
.200
5id
iopa
this
chne
in6
nein
jam
et.-
tox.
nein
134
unau
ffälli
gun
auffä
llig
post
ikta
l3.
2.20
052.
2.20
05en
tzün
dlic
hne
in0
nein
nein
entz
ündl
ich
nein
135
unau
ffälli
gun
auffä
llig
nein
jaid
iopa
this
chne
in13
6ab
norm
alab
norm
alni
cht p
ostik
tal
4.2.
2005
29.1
.200
5id
iopa
this
chne
in0
nein
jaid
iopa
this
chne
in13
7un
auffä
llig
unau
ffälli
gne
inja
idio
path
isch
nein
138
unau
ffälli
gab
norm
alni
cht p
ostik
tal
8.2.
2005
10.1
.200
5id
iopa
this
chne
in1
nein
nein
idio
path
isch
nein
139
abno
rmal
abno
rmal
post
ikta
l9.
2.20
058.
2.20
05id
iopa
this
chne
in0
nein
jaid
iopa
this
chne
in14
0un
auffä
llig
unau
ffälli
gni
cht p
ostik
tal
9.2.
2005
10.1
.200
5id
iopa
this
chne
in0
nein
nein
idio
path
isch
nein
141
unau
ffälli
gun
auffä
llig
nein
jaid
iopa
this
chne
in14
2un
auffä
llig
unau
ffälli
gne
inne
inid
iopa
this
chne
in14
3un
auffä
llig
unau
ffälli
gni
cht p
ostik
tal
9.3.
2005
20.2
.200
5id
iopa
this
chne
in0
nein
nein
idio
path
isch
nein
144
unau
ffälli
gab
norm
alpo
stik
tal
9.3.
2005
6.3.
2005
idio
path
isch
nein
0ne
inja
idio
path
isch
nein
145
abno
rmal
unau
ffälli
gne
inja
entz
ündl
ich
nein
146
abno
rmal
unau
ffälli
gpo
stik
tal
10.1
0.20
059.
10.2
005
idio
path
isch
ja0
jaja
idio
path
isch
nein
147
abno
rmal
abno
rmal
nein
jaid
iopa
this
chne
in14
8un
auffä
llig
abno
rmal
nich
t pos
tikta
l31
.3.2
005
15.3
.200
5id
iopa
this
chja
1ne
inja
idio
path
isch
nein
149
unau
ffälli
gab
norm
alpo
stik
tal
24.3
.200
523
.3.2
005
neop
last
isch
nein
2ne
inja
neop
last
isch
ja15
0un
auffä
llig
unau
ffälli
gpo
stik
tal
4.4.
2005
2.4.
2005
idio
path
isch
ja0
jaja
idio
path
isch
nein
151
abno
rmal
unau
ffälli
gne
inja
met
.-to
x.ne
in15
2un
auffä
llig
abno
rmal
post
ikta
l13
.4.2
005
11.4
.200
5id
iopa
this
chne
in0
nein
jaid
iopa
this
chne
in15
3un
auffä
llig
unau
ffälli
gni
cht p
ostik
tal
12.4
.200
58.
4.20
05id
iopa
this
chne
inne
inne
inid
iopa
this
chne
in15
4ab
norm
alun
auffä
llig
nein
nein
idio
path
isch
nein
155
abno
rmal
unau
ffälli
gne
inne
inid
iopa
this
chne
in15
6un
auffä
llig
unau
ffälli
gne
inja
idio
path
isch
nein
157
unau
ffälli
gun
auffä
llig
19.4
.200
5id
iopa
this
chne
in0
idio
path
isch
nein
158
unau
ffälli
gun
auffä
llig
nein
jaid
iopa
this
chne
in15
9ab
norm
alun
auffä
llig
nein
jam
et.-
tox.
nein
160
abno
rmal
unau
ffälli
g18
.5.2
005
neop
last
isch
nein
34ne
inja
neop
last
isch
nein
66 Appendix
Nr.
Gru
ppe
Ras
seG
esch
lech
tG
ebur
tsd.
Vor
stel
lung
sdV
orst
ella
lter
dV
orst
ella
lter
yP
robl
emat
ikA
uftr
ittsa
lter
yF
requ
enz
allg
us
161
1S
ON
ST
MK
1.1.
1997
25.4
.200
529
948,
20ge
nera
l8
erst
mal
sun
auffä
llig
162
1JR
TW
1.8.
2003
29.4
.200
562
81,
72ge
nera
l1,
5er
stm
als
unau
ffälli
g16
32
LRM
K19
.4.1
998
2.5.
2005
2533
6,94
gene
ral
1m
onat
lun
auffä
llig
164
1M
IXM
10.1
1.20
042.
5.20
0517
20,
47ge
nera
l0,
5er
stm
als
unau
ffälli
g16
52
MIX
M8.
12.1
996
9.5.
2005
3031
8,30
gene
ral
8,5
tgl
unau
ffälli
g16
62
SO
NS
TW
K30
.3.2
003
16.5
.200
576
62,
10ge
nera
l2
erst
mal
sab
norm
al16
71
SO
NS
TM
1.2.
2005
18.5
.200
510
70,
29ge
nera
l0,
25er
stm
als
unau
ffälli
g16
81
GR
M27
.7.2
001
19.5
.200
513
723,
76ge
nera
l0,
75m
onat
lun
auffä
llig
169
2W
HW
TW
K1.
1.19
9719
.5.2
005
3018
8,27
gene
ral
8,5
erst
mal
sun
auffä
llig
170
1W
HW
TM
6.11
.199
422
.5.2
005
3796
10,4
0ge
nera
l10
,5er
stm
als
abno
rmal
171
2M
IXM
K25
.5.2
002
23.5
.200
510
782,
95ge
nera
l2
unau
ffälli
g17
21
LRW
K1.
11.2
003
24.5
.200
556
31,
54ge
nera
l1,
5er
stm
als
abno
rmal
173
1R
OT
TM
1.1.
1998
25.5
.200
526
647,
30ge
nera
l7,
5er
stm
als
unau
ffälli
g17
41
TE
CK
EL
M20
.6.1
999
27.5
.200
521
375,
85ge
nera
l/kom
plex
6er
stm
als
unau
ffälli
g17
51
MIX
M18
.10.
1998
30.5
.200
523
826,
53ge
nera
l6,
5er
stm
als
unau
ffälli
g
176
1M
IXM
12.9
.200
530
.5.2
005
-102
-0,2
8ge
nera
l / fo
kal/
kom
plex
6tg
lun
auffä
llig
177
1B
EA
GLE
W24
.1.2
003
6.6.
2005
852
2,33
gene
ral
2ha
lbj
unau
ffälli
g17
82
YO
RK
W3.
1.20
028.
6.20
0512
353,
38ge
nera
l2
erst
mal
sun
auffä
llig
179
2M
IXM
K1.
1.19
9610
.6.2
005
3399
9,31
gene
ral
6w
öche
ntl
unau
ffälli
g18
01
TE
CK
EL
W13
.6.1
994
10.6
.200
539
5710
,84
gene
ral
11er
stm
als
abno
rmal
181
1S
ON
ST
WK
17.8
.199
813
.6.2
005
2456
6,73
gene
ral
3m
onat
lun
auffä
llig
182
1LR
WK
6.5.
2003
14.6
.200
575
82,
08ge
nera
l1,
5vi
erte
ljun
auffä
llig
183
1S
CH
M21
.8.2
003
15.6
.200
565
41,
79ge
nera
l2
erst
mal
sun
auffä
llig
184
1S
ON
ST
WK
26.1
0.19
9921
.6.2
005
2035
5,58
gene
ral
5jä
hrl
unau
ffälli
g18
51
MIX
M25
.1.1
998
23.6
.200
526
687,
31ge
nera
l4,
5zw
eiw
abno
rmal
186
2S
ON
ST
W12
.12.
2003
29.6
.200
555
71,
53ge
nera
l0,
5ha
lbj
unau
ffälli
g18
71
SO
NS
TM
1.1.
1996
30.6
.200
534
199,
37ge
nera
l7
wöc
hent
lun
auffä
llig
188
1S
ON
ST
M22
.5.1
994
11.7
.200
540
0910
,98
gene
ral
11er
stm
als
unau
ffälli
g18
91
MIX
WK
1.1.
1992
11.7
.200
548
7013
,34
gene
ral
13,5
erst
mal
sab
norm
al19
02
HU
SK
YM
K26
.5.1
999
19.7
.200
522
136,
06ge
nera
l4,
5zw
eiw
unau
ffälli
g19
11
CO
CK
ER
M27
.7.1
997
19.7
.200
528
727,
87ge
nera
l8
erst
mal
sun
auffä
llig
192
1S
ON
ST
WK
26.9
.199
621
.7.2
005
3175
8,70
gene
ral
4m
onat
lun
auffä
llig
193
2B
EA
GLE
WK
15.3
.200
425
.7.2
005
490
1,34
gene
ral/f
okal
1w
öche
ntl
unau
ffälli
g19
41
SO
NS
TM
18.1
2.19
9925
.7.2
005
2017
5,53
gene
ral
3w
öche
ntl
unau
ffälli
g19
51
SO
NS
TM
21.1
.200
426
.7.2
005
545
1,49
gene
ral
1zw
eiw
unau
ffälli
g19
61
SO
NS
TM
10.1
1.19
9626
.7.2
005
3136
8,59
gene
ral
6zw
eiw
unau
ffälli
g19
71
MIX
WK
1.1.
2002
27.7
.200
512
863,
52ge
nera
lun
auffä
llig
198
1M
IXW
8.3.
2003
1.8.
2005
863
2,36
gene
ral
2vi
erte
ljun
auffä
llig
199
1S
ON
ST
MK
6.5.
2002
15.8
.200
511
793,
23ge
nera
l3
mon
atl
unau
ffälli
g20
02
TE
CK
EL
M10
.1.2
002
18.8
.200
512
983,
56ge
nera
l3,
5zw
eiw
unau
ffälli
g
Appendix 67
Nr.
Labo
rne
uro
usm
rtD
atum
mrt
letz
ter
anfa
llm
rt D
iagn
ose
post
ikt.
Ver
änd.
Zel
len
liquo
rS
tatu
s ep
il.cl
uste
rE
nddi
agno
seE
utha
nasi
e16
1ab
norm
alun
auffä
llig
post
ikta
l25
.4.2
005
25.4
.200
5id
iopa
this
chne
in2
nein
jaid
iopa
this
chne
in16
2un
auffä
llig
abno
rmal
nich
t pos
tikta
l3.
5.20
0530
.4.2
005
idio
path
isch
nein
0ne
inja
idio
path
isch
nein
163
unau
ffälli
gab
norm
alne
inja
entz
ündl
ich
nein
164
unau
ffälli
gne
inja
entz
ündl
ich
ja16
5un
auffä
llig
abno
rmal
nein
nein
neop
last
isch
nein
166
abno
rmal
abno
rmal
nein
nein
met
.-to
x.ne
in16
7ab
norm
alne
inne
inA
nom
alie
nein
168
unau
ffälli
gab
norm
al8.
6.20
05id
iopa
this
chne
in0
nein
jaid
iopa
this
chne
in16
9un
auffä
llig
unau
ffälli
gja
jaid
iopa
this
chne
in17
0un
auffä
llig
abno
rmal
post
ikta
l24
.5.2
005
22.5
.200
5ne
opla
stis
chne
inja
jane
opla
stis
chve
rsto
rben
171
unau
ffälli
gun
auffä
llig
idio
path
isch
nein
172
abno
rmal
jane
inm
et.-
tox.
nein
173
abno
rmal
unau
ffälli
gni
cht p
ostik
tal
22.6
.200
517
.6.2
005
idio
path
isch
nein
0ne
inja
met
.-to
x.ne
in17
4un
auffä
llig
unau
ffälli
gni
cht p
ostik
tal
2.6.
2005
18.5
.200
5id
iopa
this
chne
in0
nein
jaid
iopa
this
chne
in17
5un
auffä
llig
unau
ffälli
gni
cht p
ostik
tal
30.5
.200
525
.5.2
005
neop
last
isch
nein
0ja
nein
neop
last
isch
nein
176
unau
ffälli
gun
auffä
llig
post
ikta
l16
.6.2
005
16.6
.200
5id
iopa
this
chne
in2
nein
jaid
iopa
this
chne
in17
7un
auffä
llig
unau
ffälli
gni
cht p
ostik
tal
7.6.
2005
17.5
.200
5id
iopa
this
chne
in0
nein
nein
idio
path
isch
nein
178
unau
ffälli
gun
auffä
llig
nein
nein
idio
path
isch
nein
179
unau
ffälli
gun
auffä
llig
nein
jaid
iopa
this
chne
in18
0un
auffä
llig
abno
rmal
jane
inm
et.-
tox.
nein
181
abno
rmal
unau
ffälli
gni
cht p
ostik
tal
24.6
.200
55.
5.20
05id
iopa
this
chne
in0
nein
nein
idio
path
isch
nein
182
abno
rmal
unau
ffälli
gni
cht p
ostik
tal
5.7.
2005
5.6.
2005
idio
path
isch
nein
1ne
inne
inid
iopa
this
chne
in18
3un
auffä
llig
abno
rmal
post
ikta
l16
.6.2
005
15.6
.200
5id
iopa
this
chne
in1
nein
jaid
iopa
this
chne
in18
4un
auffä
llig
unau
ffälli
gni
cht p
ostik
tal
28.6
.200
53.
6.20
05id
iopa
this
chne
in1
nein
nein
idio
path
isch
nein
185
unau
ffälli
gpo
stik
tal
24.6
.200
522
.6.2
005
idio
path
isch
ja1
jaja
idio
path
isch
ja18
6un
auffä
llig
unau
ffälli
gne
inne
inid
iopa
this
chne
in18
7ab
norm
alun
auffä
llig
6.7.
2005
idio
path
isch
nein
nein
nein
met
.-to
x.ja
188
abno
rmal
nein
jam
et.-
tox.
ja18
9un
auffä
llig
abno
rmal
nich
t pos
tikta
l12
.7.2
005
7.7.
2005
neop
last
isch
nein
1ne
inne
inne
opla
stis
chne
in19
0ab
norm
alun
auffä
llig
nein
jaid
iopa
this
chne
in19
1ab
norm
alab
norm
alne
inne
inm
et.-
tox.
nein
192
abno
rmal
abno
rmal
nich
t pos
tikta
l16
.8.2
005
2.7.
2007
idio
path
isch
nein
1ne
inja
neop
last
isch
nein
193
unau
ffälli
gne
inja
idio
path
isch
nein
194
abno
rmal
unau
ffälli
gni
cht p
ostik
tal
23.8
.200
518
.7.2
005
idio
path
isch
nein
1ne
inja
idio
path
isch
nein
195
abno
rmal
abno
rmal
post
ikta
l28
.7.2
005
27.7
.200
5id
iopa
this
chne
in0
nein
jaid
iopa
this
chne
in19
6ab
norm
alab
norm
alpo
stik
tal
11.8
.200
511
.8.2
005
idio
path
isch
nein
1ne
inja
idio
path
isch
nein
197
unau
ffälli
gab
norm
alni
cht p
ostik
tal
2.8.
2005
25.7
.200
5id
iopa
this
chja
nein
jaid
iopa
this
chne
in19
8un
auffä
llig
unau
ffälli
gne
inne
inm
et.-
tox.
nein
199
unau
ffälli
gun
auffä
llig
nich
t pos
tikta
l16
.8.2
005
7.8.
2005
idio
path
isch
nein
1ja
jaid
iopa
this
chne
in20
0un
auffä
llig
unau
ffälli
gne
inne
inid
iopa
this
chne
in
68 Appendix
Nr.
Gru
ppe
Ras
seG
esch
lech
tG
ebur
tsd.
Vor
stel
lung
sdV
orst
ella
lter
dV
orst
ella
lter
yP
robl
emat
ikA
uftr
ittsa
lter
yF
requ
enz
allg
us
201
2M
ÜN
ST
M29
.1.1
998
22.8
.200
527
237,
46ge
nera
l4,
5m
onat
lun
auffä
llig
202
2M
IXM
K3.
10.1
996
25.8
.200
532
028,
77ge
nera
l8
halb
jun
auffä
llig
203
1M
IXM
K1.
4.20
041.
9.20
0551
01,
40ge
nera
l1,
5er
stm
als
unau
ffälli
g20
42
MIX
M1.
1.19
985.
9.20
0527
647,
57ge
nera
l7,
5er
stm
als
unau
ffälli
g20
52
BC
M1.
10.1
999
6.9.
2005
2135
5,85
gene
ral
2zw
eiw
unau
ffälli
g20
62
SO
NS
TW
24.1
0.19
9913
.9.2
005
2119
5,81
gene
ral
6er
stm
als
unau
ffälli
g20
71
MIX
W1.
1.19
9415
.9.2
005
4214
11,5
5ge
nera
l11
,5m
onat
lun
auffä
llig
208
2S
ON
ST
M1.
7.20
0019
.9.2
005
1878
5,15
gene
ral
5er
stm
als
unau
ffälli
g20
91
SO
NS
TW
K22
.4.2
001
20.9
.200
515
884,
35ge
nera
l4
mon
atl
unau
ffälli
g21
02
BR
AC
KE
WK
10.9
.199
920
.9.2
005
2170
5,95
gene
ral
4,5
zwei
wun
auffä
llig
211
1JR
TW
6.6.
2005
20.9
.200
510
40,
28ge
nera
l0,
25er
stm
als
abno
rmal
212
1C
OC
KE
RM
K25
.8.2
002
26.9
.200
511
113,
04ge
nera
l3
mon
atl
unau
ffälli
g21
31
SO
NS
TM
6.5.
2005
6.10
.200
515
00,
41ge
nera
l0,
25tg
lab
norm
al21
42
MIX
W12
.12.
2004
8.10
.200
529
60,
81ge
nera
l1
erst
mal
sun
auffä
llig
215
1S
ON
ST
M17
.11.
2003
13.1
0.20
0568
61,
88ge
nera
l2
mon
atl
unau
ffälli
g21
61
SO
NS
TW
1.6.
1992
16.1
0.20
0548
1513
,19
gene
ral
13tg
lun
auffä
llig
217
2M
IXM
9.8.
2000
24.1
0.20
0518
755,
14ge
nera
l2
zwei
wun
auffä
llig
218
2LR
M1.
1.20
0024
.10.
2005
2093
5,73
gene
ral
3,5
jähr
lun
auffä
llig
219
1M
IXM
1.5.
2000
25.1
0.20
0519
745,
41ge
nera
l0,
5ha
lbj
unau
ffälli
g22
01
MIX
M1.
1.20
0226
.10.
2005
1375
3,77
gene
ral
3m
onat
lun
auffä
llig
221
1M
IXW
K1.
1.19
981.
11.2
005
2820
7,73
gene
ral
7w
öche
ntl
abno
rmal
222
1R
OT
TW
5.9.
1997
1.11
.200
529
368,
04ge
nera
l7
erst
mal
sun
auffä
llig
223
2M
IXM
27.4
.200
411
.11.
2005
554
1,52
gene
ral
1m
onat
l22
41
SE
TT
ER
M28
.2.1
999
14.1
1.20
0524
146,
61ge
nera
l5,
5vi
erte
ljun
auffä
llig
225
2B
EA
GLE
M4.
4.20
0114
.11.
2005
1660
4,55
gene
ral
1,5
mon
atl
unau
ffälli
g22
62
LRM
19.1
0.20
0314
.11.
2005
745
2,04
gene
ral/f
okal
1,5
mon
atl
unau
ffälli
g22
72
PU
DE
LM
15.9
.199
616
.11.
2005
3301
9,04
gene
ral
9ha
lbj
unau
ffälli
g22
81
DS
HW
13.1
0.19
9618
.11.
2005
3275
8,97
gene
ral
9er
stm
als
unau
ffälli
g22
91
YO
RK
WK
31.3
.200
029
.11.
2005
2039
5,59
gene
ral/f
okal
2,5
unau
ffälli
g23
01
BO
XE
RW
16.1
2.19
932.
12.2
005
4306
11,8
0ge
nera
l12
erst
mal
sun
auffä
llig
231
1M
IXW
1.1.
2002
6.12
.200
514
153,
88ge
nera
ler
stm
als
unau
ffälli
g23
22
MIX
M16
.10.
1997
8.12
.200
529
328,
03ge
nera
l7,
5vi
erte
ljun
auffä
llig
233
2M
ÜN
ST
M15
.12.
1996
12.1
2.20
0532
378,
87ge
nera
l9
erst
mal
sun
auffä
llig
234
1S
ON
ST
M1.
2.20
0512
.12.
2005
311
0,85
gene
ral
0,5
zwei
wab
norm
al23
51
TE
CK
EL
M12
.3.2
004
13.1
2.20
0563
11,
73ge
nera
l1,
5zw
eiw
unau
ffälli
g23
61
BR
AC
KE
WK
1.3.
2003
19.1
2.20
0510
082,
76ge
nera
l1,
5w
öche
ntl
unau
ffälli
g23
71
MIX
M6.
10.2
005
20.1
2.20
0574
0,20
gene
ral
0,25
erst
mal
sun
auffä
llig
238
2M
IXW
5.8.
1995
22.1
2.20
0537
3710
,24
gene
ral
10er
stm
als
unau
ffälli
g23
91
GR
WK
9.2.
1995
30.1
2.20
0539
2110
,74
foka
l11
erst
mal
sun
auffä
llig
240
1R
OT
TM
K1.
1.19
9830
.12.
2005
2879
7,89
gene
ral
8er
stm
als
unau
ffälli
g
Appendix 69
Nr.
Labo
rne
uro
usm
rtD
atum
mrt
letz
ter
anfa
llm
rt D
iagn
ose
post
ikt.
Ver
änd.
Zel
len
liquo
rS
tatu
s ep
il.cl
uste
rE
nddi
agno
seE
utha
nasi
e20
1un
auffä
llig
unau
ffälli
gne
inne
inid
iopa
this
chne
in20
2ab
norm
alun
auffä
llig
nein
nein
idio
path
isch
nein
203
abno
rmal
nein
nein
met
.-to
x.ne
in20
4un
auffä
llig
abno
rmal
nein
nein
met
.-to
x.ne
in20
5ab
norm
alab
norm
alne
inne
inid
iopa
this
chve
rsto
rben
206
unau
ffälli
gun
auffä
llig
nein
nein
idio
path
isch
nein
207
abno
rmal
abno
rmal
nein
nein
met
.-to
x.ne
in20
8un
auffä
llig
abno
rmal
nein
nein
entz
ündl
ich
nein
209
unau
ffälli
gun
auffä
llig
nich
t pos
tikta
l27
.9.2
005
20.9
.200
5id
iopa
this
chne
in0
nein
nein
idio
path
isch
nein
210
unau
ffälli
gun
auffä
llig
nein
jaid
iopa
this
chne
in21
1ab
norm
alab
norm
alpo
stik
tal
21.9
.200
521
.9.2
005
idio
path
isch
nein
nein
jaen
tzün
dlic
hja
212
unau
ffälli
gun
auffä
llig
nich
t pos
tikta
l25
.10.
2005
24.9
.200
5id
iopa
this
chne
in0
nein
nein
idio
path
isch
nein
213
abno
rmal
abno
rmal
post
ikta
l7.
10.2
005
7.10
.200
5id
iopa
this
chne
in24
nein
jaen
tzün
dlic
hve
rsto
rben
214
unau
ffälli
gab
norm
alne
inja
idio
path
isch
nein
215
unau
ffälli
gun
auffä
llig
nich
t pos
tikta
l14
.10.
2005
15.9
.200
5id
iopa
this
chne
in0
nein
nein
idio
path
isch
nein
216
abno
rmal
jaja
met
.-to
x.ja
217
abno
rmal
unau
ffälli
gne
inne
inid
iopa
this
chne
in21
8un
auffä
llig
unau
ffälli
gne
inne
inid
iopa
this
chne
in21
9un
auffä
llig
unau
ffälli
gne
inne
inid
iopa
this
chne
in22
0un
auffä
llig
unau
ffälli
gne
inne
inm
et.-
tox.
nein
221
abno
rmal
abno
rmal
post
ikta
l2.
11.2
005
31.1
0.20
05ne
opla
stis
chne
inne
inne
inne
opla
stis
chja
222
abno
rmal
abno
rmal
4.11
.200
5id
iopa
this
chne
in0
nein
jaid
iopa
this
chne
in22
3ab
norm
alun
auffä
llig
nein
nein
idio
path
isch
nein
224
unau
ffälli
gun
auffä
llig
nich
t pos
tikta
l14
.11.
2005
1.11
.200
5id
iopa
this
chne
in0
nein
nein
idio
path
isch
nein
225
unau
ffälli
gun
auffä
llig
jane
inid
iopa
this
chne
in22
6un
auffä
llig
unau
ffälli
gne
inne
inid
iopa
this
chne
in22
7ab
norm
alab
norm
alja
jane
opla
stis
chja
228
unau
ffälli
gun
auffä
llig
post
ikta
l18
.11.
2005
17.1
1.20
05ne
opla
stis
chne
in0
nein
nein
neop
last
isch
nein
229
unau
ffälli
gab
norm
alpo
stik
tal
13.1
2.20
0512
.12.
2005
idio
path
isch
nein
0ne
inne
inid
iopa
this
chne
in23
0un
auffä
llig
post
ikta
l5.
12.2
005
2.12
.200
5ne
opla
stis
chne
inne
inja
neop
last
isch
nein
231
abno
rmal
nein
nein
met
.-to
x.ne
in23
2un
auffä
llig
unau
ffälli
gne
inne
inid
iopa
this
chne
in23
3un
auffä
llig
unau
ffälli
gne
inja
idio
path
isch
nein
234
unau
ffälli
gun
auffä
llig
post
ikta
l20
.12.
2005
19.1
2.20
05id
iopa
this
chne
in0
nein
jaid
iopa
this
chne
in23
5ab
norm
alun
auffä
llig
nich
t pos
tikta
l20
.12.
2005
14.1
2.20
05id
iopa
this
chne
in1
nein
nein
idio
path
isch
nein
236
unau
ffälli
gun
auffä
llig
post
ikta
l19
.12.
2005
18.1
2.20
05id
iopa
this
chja
0ne
inja
idio
path
isch
nein
237
abno
rmal
nich
t pos
tikta
l29
.12.
2005
22.1
2.20
05id
iopa
this
chne
in0
nein
jam
et.-
tox.
nein
238
abno
rmal
abno
rmal
nein
nein
neop
last
isch
nein
239
unau
ffälli
gun
auffä
llig
nein
jam
et.-
tox.
nein
240
abno
rmal
unau
ffälli
gni
cht p
ostik
tal
3.1.
2006
30.1
2.20
05id
iopa
this
chne
in1
nein
nein
idio
path
isch
nein
70 Appendix
Nr.
Gru
ppe
Ras
seG
esch
lech
tG
ebur
tsd.
Vor
stel
lung
sdV
orst
ella
lter
dV
orst
ella
lter
yP
robl
emat
ikA
uftr
ittsa
lter
yF
requ
enz
allg
us
241
2S
ON
ST
M22
.8.2
000
9.1.
2006
1937
5,31
kom
pl.
5tg
lun
auffä
llig
242
2B
RA
CK
EW
6.6.
2005
10.1
.200
621
40,
59ge
nera
l0,
5zw
eiw
unau
ffälli
g24
32
YO
RK
M9.
6.20
0011
.1.2
006
2012
5,51
gene
ral
0,5
tgl
unau
ffälli
g24
42
SO
NS
TM
23.9
.200
116
.1.2
006
1553
4,25
gene
ral
4ha
lbj
unau
ffälli
g24
51
SO
NS
TW
1.1.
1996
17.1
.200
636
169,
91ge
nera
l11
wöc
hent
lun
auffä
llig
246
1LR
W25
.9.1
997
17.1
.200
629
928,
20ge
nera
l4
halb
jun
auffä
llig
247
1M
IXM
17.1
0.19
9226
.1.2
006
4779
13,0
9ge
nera
l13
erst
mal
sab
norm
al24
81
GR
W19
.12.
2004
31.1
.200
640
21,
10ge
nera
l1
zwei
wab
norm
al24
92
SC
HW
10.2
.200
131
.1.2
006
1791
4,91
gene
ral
5w
öche
ntl
unau
ffälli
g25
02
SO
NS
TM
21.5
.200
32.
2.20
0697
12,
66ge
nera
l1,
5zw
eiw
unau
ffälli
g25
11
GR
M1.
9.20
042.
2.20
0651
11,
40ge
nera
l1,
5er
stm
als
abno
rmal
252
1M
IXW
1.1.
2000
3.2.
2006
2192
6,01
gene
ral/k
ompl
ex5
tgl
unau
ffälli
g25
31
YO
RK
W15
.3.1
996
3.2.
2006
3558
9,75
gene
ral
10er
stm
als
unau
ffälli
g25
42
TE
CK
EL
W23
.8.1
994
5.2.
2006
4122
11,2
9ge
nera
l11
,5er
stm
als
abno
rmal
255
2M
IXM
K6.
12.2
000
6.2.
2006
1860
5,10
gene
ral
5er
stm
als
unau
ffälli
g25
61
SO
NS
TW
14.4
.200
59.
2.20
0629
50,
81ge
nera
l1
zwei
wun
auffä
llig
257
1JR
TM
18.1
.200
315
.2.2
006
1107
3,03
gene
ral
1,5
zwei
wun
auffä
llig
258
1M
IXM
K1.
1.19
9828
.2.2
006
2937
8,05
gene
ral
8er
stm
als
unau
ffälli
g25
92
MIX
WK
1.1.
1999
5.3.
2006
2584
7,08
gene
ral
6w
öche
ntl
unau
ffälli
g26
02
MIX
WK
1.9.
1990
7.3.
2006
5586
15,3
0ge
nera
l15
,5er
stm
als
abno
rmal
261
2B
OX
ER
WK
7.3.
2002
7.3.
2006
1440
3,95
kom
pl.
m
onat
lun
auffä
llig
262
1S
ON
ST
M5.
3.19
9813
.3.2
006
2888
7,91
foka
l8
erst
mal
sun
auffä
llig
263
2S
ON
ST
M23
.4.2
005
14.3
.200
632
10,
88ge
nera
l1
erst
mal
sun
auffä
llig
264
2S
ON
ST
MK
17.4
.199
516
.3.2
006
3929
10,7
6ge
nera
l10
,5zw
eiw
unau
ffälli
g26
51
SO
NS
TW
K19
.1.2
002
31.3
.200
615
124,
14ge
nera
l4
mon
atl
unau
ffälli
g26
61
SO
NS
TW
17.4
.200
52.
4.20
0634
50,
95ge
nera
l1
erst
mal
sab
norm
al26
72
BE
AG
LEM
26.3
.200
32.
4.20
0610
862,
98ge
nera
l3
erst
mal
sun
auffä
llig
268
2S
ON
ST
MK
29.1
0.20
033.
4.20
0687
42,
39ge
nera
l1
vier
telj
unau
ffälli
g26
91
GR
M4.
11.2
005
6.4.
2006
152
0,42
gene
ral
0,25
tgl
unau
ffälli
g27
02
WH
WT
W27
.6.2
001
10.4
.200
617
234,
72ge
nera
l4
wöc
hent
lun
auffä
llig
271
1B
EA
GLE
M30
.4.2
004
13.4
.200
670
31,
93ge
nera
l2
vier
telj
unau
ffälli
g27
22
SO
NS
TW
3.5.
2002
13.4
.200
614
203,
89ge
nera
l4
jähr
lun
auffä
llig
273
2S
ON
ST
M14
.9.2
004
18.4
.200
657
41,
57ge
nera
l1,
5w
öche
ntl
unau
ffälli
g27
41
MIX
WK
19.7
.199
918
.4.2
006
2429
6,65
gene
ral
6vi
erte
ljun
auffä
llig
275
1S
ET
TE
RW
1.1.
1996
19.4
.200
637
0810
,16
gene
ral
10er
stm
als
abno
rmal
276
1S
CH
M14
.1.2
005
25.4
.200
646
11,
26ge
nera
l0,
25tg
lun
auffä
llig
277
1M
IXW
K1.
11.1
996
25.4
.200
634
149,
35ge
nera
l9,
5er
stm
als
unau
ffälli
g27
81
SO
NS
TW
22.1
2.20
0225
.4.2
006
1203
3,30
gene
ral
3er
stm
als
unau
ffälli
g27
91
TE
CK
EL
WK
30.4
.200
6
foka
l11
mon
atl
unau
ffälli
g28
01
MIX
MK
30.6
.199
55.
5.20
0639
0510
,70
gene
ral
11er
stm
als
unau
ffälli
g
Appendix 71
Nr.
Labo
rne
uro
usm
rtD
atum
mrt
letz
ter
anfa
llm
rt D
iagn
ose
post
ikt.
Ver
änd.
Zel
len
liquo
rS
tatu
s ep
il.cl
uste
rE
nddi
agno
seE
utha
nasi
e24
1ab
norm
alun
auffä
llig
nein
nein
idio
path
isch
nein
242
unau
ffälli
gun
auffä
llig
nein
jaid
iopa
this
chne
in24
3ab
norm
alun
auffä
llig
nein
nein
idio
path
isch
nein
244
unau
ffälli
gun
auffä
llig
nein
nein
idio
path
isch
nein
245
abno
rmal
unau
ffälli
gne
inne
inm
et.-
tox.
nein
246
unau
ffälli
gun
auffä
llig
nich
t pos
tikta
l18
.1.2
006
1.12
.200
5id
iopa
this
chne
in0
nein
nein
idio
path
isch
nein
247
abno
rmal
post
ikta
l26
.1.2
006
26.1
.200
6va
skul
ärne
in0
jaja
vask
ulär
nein
248
unau
ffälli
gun
auffä
llig
nich
t pos
tikta
l16
.3.2
006
10.3
.200
6id
iopa
this
chne
in1
nein
nein
idio
path
isch
nein
249
abno
rmal
unau
ffälli
gne
inne
inid
iopa
this
chne
in25
0un
auffä
llig
unau
ffälli
gne
inja
idio
path
isch
nein
251
abno
rmal
jane
inm
et.-
tox.
nein
252
abno
rmal
unau
ffälli
gni
cht p
ostik
tal
7.2.
2006
3.2.
2006
idio
path
isch
nein
0ne
inja
idio
path
isch
nein
253
unau
ffälli
gun
auffä
llig
nich
t pos
tikta
l7.
2.20
063.
2.20
06id
iopa
this
chne
in1
jaja
idio
path
isch
nein
254
abno
rmal
abno
rmal
jane
inne
opla
stis
chja
255
unau
ffälli
gun
auffä
llig
nein
nein
idio
path
isch
nein
256
unau
ffälli
gun
auffä
llig
post
ikta
l8.
3.20
068.
3.20
06id
iopa
this
chne
in0
jaja
idio
path
isch
nein
257
unau
ffälli
gun
auffä
llig
nich
t pos
tikta
l16
.2.2
006
16.1
.200
6id
iopa
this
chne
in0
nein
jaid
iopa
this
chne
in25
8ab
norm
alja
jade
gene
rativ
ja25
9ab
norm
alab
norm
alja
jaen
tzün
dlic
hne
in26
0ab
norm
alun
auffä
llig
jane
inid
iopa
this
chne
in26
1un
auffä
llig
unau
ffälli
gid
iopa
this
chne
in26
2un
auffä
llig
unau
ffälli
gne
inne
inm
et.-
tox.
nein
263
unau
ffälli
gun
auffä
llig
nein
nein
idio
path
isch
nein
264
unau
ffälli
gun
auffä
llig
nein
nein
idio
path
isch
nein
265
abno
rmal
unau
ffälli
gne
inne
inm
et.-
tox.
nein
266
unau
ffälli
gne
inne
inm
et.-
tox.
nein
267
abno
rmal
unau
ffälli
gja
nein
idio
path
isch
nein
268
unau
ffälli
gun
auffä
llig
nein
nein
idio
path
isch
nein
269
unau
ffälli
gun
auffä
llig
post
ikta
l7.
4.20
065.
4.20
06id
iopa
this
chne
in0
nein
jaid
iopa
this
chne
in27
0un
auffä
llig
unau
ffälli
gne
inne
inid
iopa
this
chne
in27
1un
auffä
llig
unau
ffälli
gpo
stik
tal
18.7
.200
615
.7.2
006
idio
path
isch
nein
0ne
inne
inid
iopa
this
chne
in27
2un
auffä
llig
unau
ffälli
gne
inne
inid
iopa
this
chne
in27
3un
auffä
llig
unau
ffälli
gne
inne
inid
iopa
this
chne
in27
4un
auffä
llig
unau
ffälli
gpo
stik
tal
20.4
.200
620
.4.2
006
neop
last
isch
nein
0ne
inja
neop
last
isch
ja27
5un
auffä
llig
jaja
met
.-to
x.ja
276
abno
rmal
abno
rmal
27.4
.200
6A
nom
alie
nein
0ne
inja
Ano
mal
ieja
277
unau
ffälli
gpo
stik
tal
26.4
.200
625
.04.
200
idio
path
isch
nein
0ja
jaid
iopa
this
chne
in27
8un
auffä
llig
abno
rmal
post
ikta
l27
.4.2
006
25.4
.200
6en
tzün
dlic
hne
in6
nein
jaen
tzün
dlic
hne
in27
9ab
norm
alne
inja
met
.-to
x.ne
in28
0ab
norm
alun
auffä
llig
12.5
.200
6id
iopa
this
chne
in0
nein
nein
met
.-to
x.ne
in
72 Appendix
Nr.
Gru
ppe
Ras
seG
esch
lech
tG
ebur
tsd.
Vor
stel
lung
sdV
orst
ella
lter
dV
orst
ella
lter
yP
robl
emat
ikA
uftr
ittsa
lter
yF
requ
enz
allg
us
281
2S
CH
M30
.3.2
002
9.5.
2006
1479
4,05
gene
ral
3,5
jähr
lun
auffä
llig
282
1M
IXM
30.3
.200
610
.5.2
006
400,
11ge
nera
l0,
2tg
lab
norm
al28
32
SO
NS
TM
21.1
0.20
0514
.5.2
006
203
0,56
gene
ral
0,5
erst
mal
sun
auffä
llig
284
1S
ON
ST
W13
.5.2
004
15.5
.200
672
21,
98ge
nera
l1,
5zw
eiw
abno
rmal
285
1S
ON
ST
W1.
2.19
9520
.5.2
006
4069
11,1
5ge
nera
l11
erst
mal
sab
norm
al28
61
PU
DE
LM
1.1.
2000
24.5
.200
623
036,
31ge
nera
l5,
5er
stm
als
unau
ffälli
g28
72
DS
HM
K1.
11.2
003
29.5
.200
692
82,
54ge
nera
l2,
5er
stm
als
unau
ffälli
g28
81
BC
M19
.1.2
005
30.5
.200
649
11,
35ge
nera
l1
wöc
hent
lun
auffä
llig
289
2P
UD
EL
M29
.10.
2000
31.5
.200
620
125,
51ge
nera
l4,
5m
onat
lun
auffä
llig
290
1S
ON
ST
WK
1.7.
1993
31.5
.200
646
5012
,74
gene
ral/f
okal
13er
stm
als
unau
ffälli
g29
12
TE
CK
EL
M11
.11.
2002
31.5
.200
612
803,
51ge
nera
l2,
5zw
eiw
unau
ffälli
g29
21
BO
XE
RM
K1.
1.20
003.
6.20
0623
126,
33ge
nera
l6,
5w
öche
ntl
unau
ffälli
g29
31
MIX
M1.
3.19
996.
6.20
0626
157,
16fo
kal/k
ompl
ex6
unau
ffälli
g29
41
BE
AG
LEW
28.4
.200
69.
6.20
0641
0,11
gene
ral
0,2
tgl
unau
ffälli
g29
51
MIX
M1.
1.19
9813
.6.2
006
3042
8,33
gene
ral
2m
onat
lun
auffä
llig
296
1JR
TW
30.9
.200
418
.6.2
006
618
1,69
gene
ral
2er
stm
als
unau
ffälli
g29
71
HU
SK
YW
K1.
1.20
0019
.6.2
006
2328
6,38
gene
ral
5un
auffä
llig
298
2T
EC
KE
LM
27.4
.200
419
.6.2
006
772
2,12
gene
ral
2m
onat
lun
auffä
llig
299
2B
RA
CK
EW
16.3
.200
323
.6.2
006
1177
3,22
gene
ral
2,5
mon
atl
unau
ffälli
g30
01
SO
NS
TW
1.1.
2003
26.6
.200
612
553,
44ge
nera
l3,
5er
stm
als
abno
rmal
301
1M
IXW
1.5.
2003
26.6
.200
611
353,
11ge
nera
l1,
5w
öche
ntl
unau
ffälli
g30
21
RO
TT
M27
.4.1
998
27.6
.200
629
408,
05ge
nera
l7,
5m
onat
lab
norm
al30
31
SO
NS
TW
1.1.
1993
29.6
.200
648
5813
,31
gene
ral
13,5
tgl
unau
ffälli
g30
41
GR
W6.
7.19
9630
.6.2
006
3594
9,85
gene
ral
10er
stm
als
abno
rmal
305
1M
IXM
K1.
1.20
043.
7.20
0690
22,
47ge
nera
l2,
5w
öche
ntl
unau
ffälli
g30
62
GR
WK
1.5.
1996
3.7.
2006
3662
10,0
3ge
nera
l10
erst
mal
sun
auffä
llig
307
2M
IXW
1.1.
2001
3.7.
2006
1982
5,43
gene
ral
4vi
erte
ljun
auffä
llig
308
1S
ON
ST
W6.
1.20
066.
7.20
0618
00,
49ge
nera
l0,
2w
öche
ntl
unau
ffälli
g30
91
SC
HW
8.4.
2006
13.7
.200
695
0,26
gene
ral
0,25
erst
mal
sab
norm
al31
02
SO
NS
TM
K22
.4.1
999
14.7
.200
626
027,
13ge
nera
l3
mon
atl
unau
ffälli
g31
12
BO
XE
RW
29.7
.199
621
.7.2
006
3592
9,84
gene
ral/k
ompl
ex10
tgl
unau
ffälli
g31
21
JRT
M1.
5.19
9723
.7.2
006
3322
9,10
gene
ral
9er
stm
als
abno
rmal
313
1G
RW
K14
.11.
1998
24.7
.200
627
707,
59ge
nera
l7,
5m
onat
lun
auffä
llig
314
1S
ON
ST
WK
1.3.
1994
28.7
.200
644
6712
,24
gene
ral
12er
stm
als
unau
ffälli
g31
52
YO
RK
M14
.2.2
006
29.7
.200
616
50,
45ge
nera
l0,
5er
stm
als
unau
ffälli
g31
62
MIX
W1.
1.19
9430
.7.2
006
4529
12,4
1ge
nera
lun
auffä
llig
317
1Y
OR
KW
27.1
2.20
0530
.7.2
006
213
0,58
gene
ral
0,75
erst
mal
sab
norm
al31
82
GR
W16
.4.2
000
1.8.
2006
2265
6,21
gene
ral
6er
stm
als
unau
ffälli
g31
91
GR
M7.
8.19
973.
8.20
0632
368,
87fo
kal
9er
stm
als
unau
ffälli
g32
01
SO
NS
TM
13.4
.200
65.
8.20
0611
20,
31ge
nera
l0,
25er
stm
als
unau
ffälli
g
Appendix 73
Nr.
Labo
rne
uro
usm
rtD
atum
mrt
letz
ter
anfa
llm
rt D
iagn
ose
post
ikt.
Ver
änd.
Zel
len
liquo
rS
tatu
s ep
il.cl
uste
rE
nddi
agno
seE
utha
nasi
e28
1un
auffä
llig
unau
ffälli
gne
inne
inid
iopa
this
chne
in28
2ab
norm
alja
jaen
tzün
dlic
hja
283
abno
rmal
unau
ffälli
gne
inja
idio
path
isch
nein
284
abno
rmal
abno
rmal
nich
t pos
tikta
l11
.7.2
006
27.6
.200
6A
nom
alie
nein
0ne
inja
Ano
mal
iene
in28
5ab
norm
alab
norm
alpo
stik
tal
23.5
.200
620
.5.2
006
vask
ulär
nein
0ne
inne
inva
skul
ärne
in28
6ab
norm
alab
norm
alpo
stik
tal
26.5
.200
626
.5.2
006
idio
path
isch
nein
7166
nein
jaen
tzün
dlic
hja
287
abno
rmal
unau
ffälli
gne
inja
idio
path
isch
nein
288
unau
ffälli
gun
auffä
llig
post
ikta
l31
.5.2
006
28.5
.200
6id
iopa
this
chne
in0
nein
jaid
iopa
this
chne
in28
9ab
norm
alun
auffä
llig
nein
jaid
iopa
this
chne
in29
0ab
norm
alab
norm
alni
cht p
ostik
tal
1.6.
2006
22.5
.200
6ne
opla
stis
chne
inne
inja
neop
last
isch
nein
291
unau
ffälli
gab
norm
alne
inja
idio
path
isch
nein
292
unau
ffälli
gun
auffä
llig
post
ikta
l7.
7.20
066.
7.20
06ne
opla
stis
chne
inja
jane
opla
stis
chne
in29
3un
auffä
llig
unau
ffälli
gne
inne
inm
et.-
tox.
nein
294
abno
rmal
unau
ffälli
gpo
stik
tal
13.6
.200
612
.6.2
006
idio
path
isch
nein
1ne
inja
idio
path
isch
nein
295
unau
ffälli
gun
auffä
llig
nich
t pos
tikta
l22
.6.2
006
4.6.
2006
idio
path
isch
nein
6ne
inne
inen
tzün
dlic
hne
in29
6ab
norm
alab
norm
alne
inja
met
.-to
x.ne
in29
7un
auffä
llig
unau
ffälli
gni
cht p
ostik
tal
27.6
.200
61.
6.20
06id
iopa
this
chne
in1
nein
nein
idio
path
isch
nein
298
unau
ffälli
gun
auffä
llig
nein
nein
idio
path
isch
nein
299
unau
ffälli
gun
auffä
llig
nein
nein
idio
path
isch
nein
300
unau
ffälli
gab
norm
alpo
stik
tal
26.6
.200
624
.6.2
006
Ano
mal
iene
inne
inne
inA
nom
alie
nein
301
unau
ffälli
gun
auffä
llig
nich
t pos
tikta
l5.
7.20
0629
.5.2
006
idio
path
isch
nein
0ja
jaid
iopa
this
chne
in30
2un
auffä
llig
unau
ffälli
gne
inja
neop
last
isch
nein
303
abno
rmal
unau
ffälli
gne
inja
met
.-to
x.ne
in30
4ab
norm
alun
auffä
llig
nein
nein
met
.-to
x.ne
in30
5ab
norm
alun
auffä
llig
post
ikta
l4.
7.20
052.
7.20
06id
iopa
this
chne
in1
nein
jaid
iopa
this
chne
in30
6un
auffä
llig
abno
rmal
nein
nein
neop
last
isch
nein
307
unau
ffälli
gun
auffä
llig
jaja
idio
path
isch
nein
308
unau
ffälli
gpo
stik
tal
6.7.
2005
6.7.
2006
idio
path
isch
nein
0ne
inja
idio
path
isch
nein
309
abno
rmal
abno
rmal
nein
nein
met
.-to
x.ne
in31
0ab
norm
alun
auffä
llig
nein
jaid
iopa
this
chne
in31
1un
auffä
llig
abno
rmal
jaja
neop
last
isch
nein
312
abno
rmal
abno
rmal
jaja
met
.-to
x.ne
in31
3un
auffä
llig
unau
ffälli
gni
cht p
ostik
tal
25.7
.200
617
.7.2
006
idio
path
isch
nein
0ne
inne
inid
iopa
this
chne
in31
4ab
norm
alab
norm
alni
cht p
ostik
tal
15.3
.200
628
.7.2
006
idio
path
isch
nein
16ne
inne
inen
tzün
dlic
hne
in31
5ab
norm
alab
norm
alne
inne
inm
et.-
tox.
nein
316
abno
rmal
abno
rmal
nein
nein
neop
last
isch
nein
317
abno
rmal
unau
ffälli
gne
inja
met
.-to
x.ne
in31
8ab
norm
alab
norm
alne
inne
inne
opla
stis
chja
319
unau
ffälli
gun
auffä
llig
post
ikta
l4.
8.20
063.
8.20
06ne
opla
stis
chne
in0
nein
nein
neop
last
isch
nein
320
abno
rmal
jaja
met
.-to
x.ne
in
74 Appendix
Nr.
Gru
ppe
Ras
seG
esch
lech
tG
ebur
tsd.
Vor
stel
lung
sdV
orst
ella
lter
dV
orst
ella
lter
yP
robl
emat
ikA
uftr
ittsa
lter
yF
requ
enz
allg
us
321
1S
ON
ST
M11
.9.2
004
7.8.
2006
686
1,88
gene
ral
2m
onat
lun
auffä
llig
322
1Y
OR
KM
K29
.7.2
000
10.8
.200
621
715,
95ge
nera
l6
tgl
unau
ffälli
g32
31
SO
NS
TM
7.6.
1999
14.8
.200
625
877,
09ge
nera
l7
mon
atl
unau
ffälli
g32
41
BR
AC
KE
M2.
10.2
003
17.8
.200
610
352,
84ge
nera
l1,
5vi
erte
ljun
auffä
llig
325
2R
OT
TW
9.4.
2006
21.8
.200
613
20,
36ge
nera
l0,
25er
stm
als
unau
ffälli
g32
62
JRT
W8.
5.20
0222
.8.2
006
1544
4,23
gene
ral
4zw
eiw
unau
ffälli
g32
71
SO
NS
TM
10.5
.199
722
.8.2
006
3342
9,16
gene
ral
9m
onat
lun
auffä
llig
328
2H
US
KY
M25
.6.2
005
22.8
.200
641
71,
14ge
nera
l1
wöc
hent
lun
auffä
llig
329
1M
ÜN
ST
M1.
1.20
0422
.8.2
006
951
2,61
gene
ral
2,5
erst
mal
sun
auffä
llig
330
1M
IXW
27.9
.200
128
.8.2
006
1771
4,85
gene
ral
5tg
lun
auffä
llig
331
2C
OC
KE
RW
11.2
.200
629
.8.2
006
198
0,54
gene
ral
0,25
vier
telj
unau
ffälli
g33
22
SO
NS
TM
5.11
.200
129
.8.2
006
1734
4,75
foka
l5
erst
mal
sun
auffä
llig
333
1M
IXW
19.1
2.20
032.
9.20
0697
32,
67ge
nera
l3
erst
mal
sun
auffä
llig
334
1D
SH
W23
.7.2
004
4.9.
2006
761
2,08
gene
ral
0,25
mon
atl
unau
ffälli
g33
51
JRT
W6.
3.19
975.
9.20
0634
199,
37ge
nera
l9
mon
atl
unau
ffälli
g33
61
MIX
W1.
5.19
947.
9.20
0644
4612
,18
kom
pl.
11,5
unau
ffälli
g33
71
LRW
5.5.
2005
11.9
.200
648
61,
33ge
nera
l1
mon
atl
unau
ffälli
g33
82
JRT
W13
.9.2
006
gene
ral
2w
öche
ntl
unau
ffälli
g33
91
GR
W10
.3.2
003
19.9
.200
612
693,
48ge
nera
l1
mon
atl
unau
ffälli
g34
01
MIX
MK
1.2.
2004
19.9
.200
694
82,
60ge
nera
l1,
5vi
erte
ljun
auffä
llig
341
1D
SH
W31
.12.
2005
22.9
.200
626
20,
72ge
nera
l0,
75er
stm
als
abno
rmal
342
1S
ON
ST
MK
22.5
.200
124
.9.2
006
1922
5,27
gene
ral
5m
onat
lun
auffä
llig
343
1B
RA
CK
EW
7.4.
2003
26.9
.200
612
493,
42ge
nera
l3,
5m
onat
lun
auffä
llig
Lege
nd:
Nr.
= n
umbe
r, G
rupp
e =
gro
up,
Ras
se =
bre
ed,
Ges
chle
cht
= g
ende
r, G
ebur
tsd.
= d
ate
of b
irth,
Vor
stel
lung
sd.
= d
ate
of p
rese
ntat
ion,
Vor
stel
lung
salte
r d
= a
ge a
t da
te o
f pr
esen
tatio
n in
day
s, V
orst
ellu
ngsa
lter
y =
age
at
date
of
pres
enta
tion
in y
ears
, P
robl
emat
ic =
kin
d of
seiz
ures
,, A
uftr
ittsa
lter
y =
age
whe
n fir
st s
eizu
re o
ccur
red,
Fre
quen
z =
freq
uenc
y, a
llg u
s =
phys
ical
exa
min
atio
n
LR =
Lab
rado
r R
etrie
ver,
SC
H =
Sch
nauz
er, M
IX =
mix
ed b
reed
, S
ON
ST
= m
isce
llane
ous,
TE
CK
EL=
dac
hshu
nd,
WH
WT
= W
esth
ighl
and
Whi
te
Ter
rier,
GR
= G
olde
n R
etrie
ver,
RO
TT
= R
ottw
eile
r, J
RT
= J
ack
Rus
sel
Ter
rier,
MÜ
NS
T =
Mün
ster
länd
er,
SE
TT
ER
= S
ette
r, D
SH
= G
erm
an
She
pher
d, B
C =
Bor
der
Col
lie, H
US
KY
= H
usky
, B
EA
GLE
= B
eagl
e, C
OC
KE
R =
Coc
ker
Spa
niel
, Y
OR
K =
Yor
kshi
re T
errie
r, B
RA
CK
E =
Bra
cke,
BO
XE
R =
Box
er, P
UD
EL
= P
oodl
e, M
= m
ale,
MK
= n
eute
red
mal
e, W
= fe
mal
e, W
K =
neu
tere
d fe
mal
e, g
ener
al =
gen
eral
ized
sei
zure
s, /f
okal
=
foca
l sei
zure
s, k
ompl
. =
com
plex
foc
al s
eizu
res,
zw
eiw
= e
very
sec
ond
wee
k, m
onat
l = m
onth
ly,
wöc
hent
l = w
eekl
y, t
gl =
dai
ly,
vier
telj
= e
very
3
mon
ths,
ers
tmal
s =
for
the
first
tim
e, h
albj
= e
very
6 m
onth
s, u
nauf
fälli
g =
unre
mar
kabl
e, a
bnor
mal
= a
bnor
mal
Appendix 75
Nr.
Labo
rne
uro
usm
rtD
atum
mrt
letz
ter
anfa
llm
rt D
iagn
ose
post
ikt.
Ver
änd.
Zel
len
liquo
rS
tatu
s ep
il.cl
uste
rE
nddi
agno
seE
utha
nasi
e32
1un
auffä
llig
abno
rmal
post
ikta
l8.
8.20
066.
8.20
06id
iopa
this
chne
in0
nein
jaid
iopa
this
chne
in32
2ab
norm
alab
norm
alpo
stik
tal
14.8
.200
613
.8.2
006
idio
path
isch
ja2
nein
jaid
iopa
this
chne
in32
3un
auffä
llig
unau
ffälli
gni
cht p
ostik
tal
22.8
.200
67.
8.20
06id
iopa
this
chne
in0
nein
nein
idio
path
isch
nein
324
unau
ffälli
gun
auffä
llig
nein
nein
idio
path
isch
nein
325
unau
ffälli
gun
auffä
llig
idio
path
isch
nein
326
unau
ffälli
gun
auffä
llig
nein
jaid
iopa
this
chne
in32
7ab
norm
alun
auffä
llig
nein
jam
et.-
tox.
nein
328
unau
ffälli
gun
auffä
llig
nein
jaid
iopa
this
chne
in32
9ab
norm
alun
auffä
llig
jaja
met
.-to
x.ne
in33
0un
auffä
llig
nein
jam
et.-
tox.
nein
331
unau
ffälli
gun
auffä
llig
idio
path
isch
nein
332
unau
ffälli
gab
norm
alne
inja
entz
ündl
ich
nein
333
abno
rmal
abno
rmal
post
ikta
l2.
9.20
062.
9.20
06id
iopa
this
chne
inja
jam
et.-
tox.
nein
334
abno
rmal
unau
ffälli
gni
cht p
ostik
tal
14.9
.200
61.
4.20
06id
iopa
this
chne
inne
inne
inid
iopa
this
chne
in33
5un
auffä
llig
unau
ffälli
g6.
9.20
06id
iopa
this
chne
in0
nein
nein
idio
path
isch
nein
336
unau
ffälli
gab
norm
alpo
stik
tal
8.9.
2006
7.9.
2006
idio
path
isch
nein
1ne
inja
idio
path
isch
nein
337
unau
ffälli
gun
auffä
llig
nich
t pos
tikta
l12
.9.2
006
30.8
.200
6id
iopa
this
chne
in1
nein
nein
idio
path
isch
nein
338
abno
rmal
abno
rmal
jaja
entz
ündl
ich
nein
339
unau
ffälli
gab
norm
alni
cht p
ostik
tal
20.9
.200
631
.8.2
006
idio
path
isch
nein
1ne
inja
idio
path
isch
nein
340
unau
ffälli
gun
auffä
llig
nich
t pos
tikta
l26
.9.2
006
15.9
.200
6id
iopa
this
chne
inne
inne
inid
iopa
this
chne
in34
1ab
norm
alab
norm
alni
cht p
ostik
tal
27.9
.200
622
.9.2
006
entz
ündl
ich
nein
1323
nein
jaen
tzün
dlic
hne
in34
2ab
norm
alun
auffä
llig
nein
jam
et.-
tox.
nein
343
abno
rmal
unau
ffälli
gpo
stik
tal
27.9
.200
625
.9.2
006
idio
path
isch
nein
0ne
inne
inid
iopa
this
chne
in
Lege
nd: N
r. =
Lab
or =
blo
od c
ell c
ount
and
ser
um c
hem
istr
y, n
euro
us=
neu
rolo
gica
l exa
min
atio
n, m
rt =
mag
netic
res
onan
ce im
agin
g, D
atum
mrt
= d
ate
of M
RI
perf
orm
ance
, le
tzte
r A
nfal
l = la
st s
eizu
re,
mrt
Dia
gnos
e =
mri
diag
nosi
s, p
ostik
t. V
erän
d. =
pos
ticta
l cha
nges
, Z
elle
n liq
uor
= c
ells
in C
SF
, S
tatu
s ep
il. =
sta
tus
epile
ptic
us,
clus
ter
= c
lust
er r
un,
End
diag
nose
= d
iagn
osis
, E
utha
nasi
e =
eut
hana
sia,
una
uffä
llig
= u
nrem
arka
ble,
abn
orm
al =
abn
orm
al,
post
ikta
l = p
ostic
tal,
nich
t po
stik
tal
= no
n po
stic
tal,
idio
path
isch
= i
diop
athi
c ep
ileps
y, v
ascu
lar
= va
scul
ar,
entz
ündl
ich
= in
flam
mat
ory,
tra
umat
isch
= t
raum
atic
, A
nom
alie
=
anom
aly,
met
.-to
x. =
met
abol
ic-t
oxic
, neo
plas
tisch
= n
eopl
astic
, deg
ener
ativ
e =
deg
ener
ativ
e, n
ein
= n
o, ja
= y
es, v
erst
orbe
n =
pas
sed
away
76 Acknowledgements
11 Acknowledgements
Mein ganz besonderer und herzlichster Dank gilt meiner Betreuerin Frau Prof. Dr.
Andrea Tipold. Ihre durchgehend engagierte und freundschaftliche Betreuung meiner
Arbeit hat den allergrößten Anteil an deren Gelingen.
Herrn Prof. Dr. Ingo Nolte danke ich für die Möglichkeit der Durchführung dieser
Arbeit in der Klinik für Kleintiere der Stiftung Tierärztliche Hochschule Hannover.
Bei der Gesellschaft zur Förderung kynologischer Forschung bedanke ich mich für
die zur Verfügung gestellte Projektförderung.
Meinen Neurologen danke ich ganz, ganz herzlich für die geduldigen Erklärungen
und all die schönen Stunden, in denen wir immer herzhaft lachen konnten.
Auch allen anderen Mitarbeitern der Klinik für Kleintiere der Stiftung Tierärztliche
Hochschule Hannover danke ich für die unkomplizierte und nette Zusammenarbeit.
Hervorzuheben wäre jedoch die stete Geduld von Frau Littmann und Frau Thum bei
der Weiterleitung meiner Patienten-Termine.
Herrn Dr. Martin Beyerbach aus dem Institut für Biometrie, Epidemiologie und
Informationsverarbeitung der Stiftung Tierärztliche Hochschule Hannover danke ich
für die Hilfe bei der statistischen Auswertung meiner Daten.
Bei meinen „Liebsten“ Ruthi und Karla möchte ich mich vor allem dafür bedanken,
dass sie immer für mich da waren und stets ein offenes Ohr für Probleme jeglicher
Art hatten. Alle (bzw. fast alle) Prüfungen miteinander durchzustehen schweißt doch
enorm zusammen. Ihr seid die Besten!!!
Meinen „Tiermedizinern“, mittlerweile in ganz Deutschland verstreut, danke für all die
schönen und lustigen Momente im Pylorus, auf dem Campus, beim Brunchen, beim
Vorglühen, auf den Parties, beim Katerfrühstück… diese Zeit kann uns keiner mehr
nehmen!
Acknowledgements 77
Der besten WG in Hannover (Karla, Hanna und Dirk) danke ich für schönen letzten 2
Jahre- es war einfach super mit euch!
All meinen Freunden aus dem Ruhrgebiet danke ich dafür, dass sie mir in den letzten
7 Jahren stets die Treue erwiesen und mich jetzt wieder mit offenen Armen
empfangen haben.
Bei meinem lieben Schulfreund Dipl.-Ing. Dominik Wegener bedanke ich mich sehr
für die tolle Hilfe beim Formatieren dieser Arbeit. Ohne dich wäre das nicht so
einfach geworden.
Bei meinem Bruder Carsten und meiner „Schwägerin“ Sarah bedanke ich mich
besonders für meine wundervolle Nichte Lea.
Zuletzt, jedoch nicht weniger wichtig, möchte ich mich bei meiner Mutter, Dietmar,
meinen Geschwistern und meinen Großeltern für all die schönen Momente
bedanken, die wir zusammen verbracht haben.
Ich danke euch, dass ihr sowohl in einfachen als auch in schwierigeren Zeiten immer
hinter mir standet und mich unterstützt habt wo ihr nur konntet.
Meinen beiden Schwestern Yvonne und Kerstin möchte ich noch sagen- ihr schafft
das schon! Ich glaube fest an euch…